Activatable cytokine polypeptides and methods of use thereof

ABSTRACT

The disclosure features fusion proteins that are conditionally active variants of a cytokine of interest. In one aspect, the full-length polypeptides of the invention have reduced or minimal cytokine-receptor activating activity even though they contain a functional cytokine polypeptide. Upon activation, e.g., by cleavage of a linker that joins a blocking moiety, e.g. a steric blocking polypeptide, in sequence to the active cytokine, the cytokine can bind its receptor and effect signaling. Typically, the fusion proteins further comprise an in vivo half-life extension element, which may be cleaved from the cytokine in the tumor microenvironment.

This application is a continuation of U.S. patent application Ser. No. 17/741,275, filed on May 10, 2022, which is a continuation of International Patent Application No. PCT/US2020/060624, filed on Nov. 14, 2020, which claims the benefit of U.S. Provisional Application No. 62/935,605, filed on Nov. 14, 2019, each of which are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in XML format format and is hereby incorporated by reference in its entirety. Said XML file, created on Sep. 20, 2022, is named 761146_300011_SL.xml and is 908,507 bytes in size.

BACKGROUND

The development of mature immunocompetent lymphoid cells from less-committed precursors, their subsequent antigen-driven immune responses, and the suppression of these and unwanted autoreactive responses are highly dependent and regulated by cytokines (including interleukin-2 [IL-2], IL-4, IL-7, IL-9, IL-15, and IL-21) that utilize receptors in the common γ-chain (γc) family (Rochman et al., 2009) and family members including IL-12, 18 and 23. IL-2 is essential for thymic development of Treg cells and critically regulates several key aspects of mature peripheral Treg and antigen-activated conventional T cells. Because of its potent T cell growth factor activity in vitro, IL-2 has been extensively studied in part because this activity offered a potential means to directly boost immunity, e.g., in cancer and AIDS-HIV patients, or a target to antagonize unwanted responses, e.g., transplantation rejection and autoimmune diseases. Although in vitro studies with IL-2 provided a strong rationale for these studies, the function of IL-2 in vivo is clearly much more complex as first illustrated in IL-2-deficient mice, where a rapid lethal autoimmune syndrome, not lack of immunity, was observed (Sadlack et al., 1993, 1995). Similar observations were later made when the gene encoding IL-2Rα (Il2ra) and IL-2Rβ (Il2rb) were individually ablated (Suzuki et al., 1995; Willerford et al., 1995).

The present invention refers to conditionally active and/or targeted cytokines for use in the treatment of cancer and other diseases dependent on immune up or down regulation. For example, the antitumoral activity of some cytokines is well known and described and some cytokines have already been used therapeutically in humans. Cytokines such as interleukin-2 (IL-2) and interferon α (IFNα) have shown positive antitumoral activity in patients with different types of tumors, such as kidney metastatic carcinoma, hairy cell leukemia, Kaposi sarcoma, melanoma, multiple myeloma, and the like. Other cytokines like IFNβ, the Tumor Necrosis Factor (TNF) α, TNFβ, IL-1, 4, 6, 12, 15 and the CSFs have shown a certain antitumoral activity on some types of tumors and therefore are the object of further studies.

SUMMARY

Provided herein are therapeutic proteins, nucleic acids (e.g., DNA, RNA, mRNA) that encode the proteins, and compositions and methods of using the proteins and nucleic acids for the treatment of a disease or disorder, such as proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, graft-versus-host disease and the like. In certain embodiments, the fusion protein the amino acid sequence of any one of SEQ ID NOs.: 193-271. Certain fusion proteins disclosed herein are referred to as ACP200-208, ACP211, ACP213-ACP215, ACP240-ACP245, ACP247, ACP284-ACP292, ACP296-ACP300, ACP302-ACP306, ACP309-ACP314, ACP336-ACP359, ACP371-ACP379, ACP383-ACP434, ACP439-ACP447, or ACP451-ACP471. This disclosure also relates to nucleic acids (e.g., DNA, RNA, mRNA) that encode the fusion proteins, methods of making fusion proteins, compositions comprising a fusion protein, as well as methods of using the fusion proteins to treat cancer including combination of two or more fusion proteins and one or more fusion protein in combination with another therapeutic agent.

The invention features fusion proteins that are conditionally active variants of a cytokine of interest. Cytokines of particular interest include IL-2, IL-12, and IFN. In one aspect, the full-length polypeptides of the invention have reduced or minimal cytokine-receptor activating activity even though they contain a functional cytokine polypeptide. Upon activation, e.g., by cleavage of a linker that joins a blocking moiety, e.g. a steric blocking polypeptide, in sequence to the active cytokine, the cytokine, e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23, IFNalpha, IFNbeta, IFNgamma, TNFalpha, lymphotoxin, TGF-beta1, TGFbeta2, TGFbeta3, GM-CSF, CXCL10, CCL19, CCL20, CCL21 or functional fragment or mutein or functional variant or a subunit of any of the foregoing, can bind its receptor and effect signaling. If desired, the full-length polypeptides can include a blocking polypeptide moiety that also provides additional advantageous properties. For example, the full-length polypeptide can contain a blocking polypeptide moiety that also extends the serum half-life and/or targets the full-length polypeptide to a desired site of cytokine activity. Alternatively, the full-length fusion polypeptides can contain a serum half-life extension element and/or targeting domain that are distinct from the blocking polypeptide moiety. Preferably, the fusion protein contains at least one element or domain capable of extending in vivo circulating half-life. Preferably, this element is removed enzymatically in the desired body location (e.g. protease cleavage in the tumor microenvironment), restoring pharmacokinetic properties to the payload molecule (e.g. IL2, IL-12, IFNb or IFNa) substantially similar to the naturally occurring payload molecule. The fusion proteins may be targeted to a desired cell or tissue.

The fusion polypeptides typically comprise a cytokine polypeptide [A], a blocking moiety [D], optionally a half-life extension moiety [H], and a protease-cleavable polypeptide linker. The cytokine polypeptide and the blocking moiety and the optional half-life extension element when present are operably linked by the protease-cleavable polypeptide linker and the fusion polypeptide has attenuated cytokine receptor activating activity, e.g., the cytokine-receptor activating activity of the fusion polypeptide is at least about 10× less than the cytokine receptor activating activity of the polypeptide that contains the cytokine polypeptide that is produced by cleavage of the protease cleavable linker. Some preferred fusion polypeptides are of one of formula (I)-(VI):

[A]-[L1]-[H]-[L2]-[D]  (I);

[D]-[L2]-[H]-[L1]-[A]  (II);

[A]-[L1]-[D]-[L2]-[H]  (III);

[H]-[L2]-[D]-[L1]-[A]  (IV);

[H]-[L1]-[A]-[L2′]-[D]  (V);

[D]-[L1]-[A]-[L2′]-[H]  (VI);

wherein A is a cytokine polypeptide, D is a blocking moiety, H is a half-life extension moiety, L1 is a protease-cleavable polypeptide linker, L2 is an polypeptide linker that is optionally protease-cleavable, and L2′ is a protease-cleavable polypeptide linker. L1 and L2 or L1 and L2′ can be have the same or different amino acid sequence and or protease-cleavage site (when L2 is protease-cleavable) as desired.

In some aspects, the fusion proteins described herein are conditionally active variants of IL-12, IL-2, or IFN. In embodiments, the fusion protein can contain an IL-2 polypeptide. The fusion protein containing an IL-2 polypeptide can comprise or consist of the amino acid sequence of SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, and 636-646. The fusion proteins disclosed as SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388420, 579-608, 636-646 are referred to herein as ACP289-ACP292, ACP296-ACP302, WW0301, ACP304-ACP306, ACP309-ACP313, WW0353, ACP414, ACP336-ACP398, WW0472-WW0477, ACP406-ACP426, ACP439-ACP447, ACP451-ACP471, WW0729, WW0734-WW0792, ACP101, ACP293-ACP295, ACP316-ACP335, ACP427-ACP438, and ACP448-ACP450. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 272. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 286. The fusion protein can comprise the amino acid sequence of SEQ ID NO:362. The fusion protein can comprise the amino acid sequence of SEQ ID NO:336. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 348. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 363. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 580.

In embodiments, the fusion protein can contain IL-12. The fusion protein containing an IL-12 polypeptide can comprise or consist of the amino acid sequence of any one of SEQ ID NOs. 368-371, 434-440, 453-519, or 523-538. The fusion proteins disclosed as SEQ ID NOs. 368-371, 434-440, 453-519, or 523-538 are referred to herein as ACP240-ACP245, ACP247, ACP285-ACP288, WW0641, WW0649-WW0652, WW0662-WW0725, WW0765-WW0772, and WW0796-WW0803. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 424. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 428. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 541. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 556. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 560. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 568. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 573.

In embodiments, the fusion protein contains IFN. The fusion protein containing an IFN polypeptide can comprise or consist of the amino acid sequence of any one of SEQ ID NOs. 421-430, and 539-578. The fusion proteins disclosed as SEQ ID NOs. 421-430, and 539-578 can be referred to herein as ACP200-ACP209, WW0644-WW0648, WW0781-WW0786, WW0815-WW0822, WW0831-WW0834, WW0737-WW0748, and WW0787-WW0790.

In some aspects, the fusion polypeptide disclosed herein can be covalently or non-covalently bonded to a second polypeptide chain. For example, a fusion polypeptide can dimerize (i.e. form a dimer) or a portion of a fusion polypeptide may associate with another polypeptide, for example, to form a functional binding site for a cytokine polypeptide or serum albumin. In certain embodiments, the second polypeptide chain and the blocking moiety on the fusion polypeptide are complementary and together form a functional binding site that has specificity for the cytokine polypeptide contained in the fusion polypeptide. Exemplary functional binding sites that can be formed by the blocking moiety of the fusion polypeptide and a complimentary second polypeptide include antigen binding sites of antibodies, such as a Fab fragment of an antibody or a portion thereof. For example, one chain of a Fab that binds the cytokine can be the blocking moiety of the fusion polypeptide, e.g., a VH-CH1, and the complementary VL-CL can be part of the second polypeptide. In such situations, the blocking moiety of the fusion protein i.e., VH-CH1 and the second polypeptide that comprises the complementary VL-CL, can associate to form a functional binding site with specificity for the cytokine polypeptide contained within the fusion protein (e.g., IL-2, IL-12, IFNalpha, IFNbeta) and attenuate cytokine polypeptide activity.

In embodiments, the fusion protein containing an IL-2 cytokine polypeptide can be bonded covalently or noncovalently to a second polypeptide chain. The second polypeptide chain can contain an antibody light chain VL-CL that comprises or consists of the amino acid sequence of SEQ ID NO: 263, 264, or 333. Such a second polypeptide can bond with a complimentary VH-CH1 polypeptide contained within the fusion protein, e.g., as contained within SEQ ID NOS: 362, 363, 325, 286, 579, 581, or 582. The second polypeptide chain disclosed as SEQ ID NOs. 263, 264, and 333 can be referred herein as WW0523 (ACP381), WW0524 (ACP382), or WW0556 (ACP414).

In embodiments, the fusion polypeptide can comprise or consist of the amino acid sequence of SEQ ID NOs. 362, 363, 325, 286, 579, 581, or 582 and the second polypeptide chain can comprise or consist of the amino acid sequence of SEQ ID NOs: 263, 264, or 333. The fusion polypeptide disclosed as SEQ ID NOs. 362, 363, 325, 286, 579, 581, or 582 can be referred to as WW0520 (ACP378), WW0521 (ACP379), WW0548 (ACP406), WW0621 (ACP457), WW0729, WW0735, or WW0736, and the second polypeptide chain disclosed as SEQ ID NOs. 263, 264, and 333 can be referred herein as WW0523 (ACP381), WW0524 (ACP382), or WW0556 (ACP414). For example, the fusion protein can comprise or consist the amino acid sequence of SEQ ID NO: 362 and the second polypeptide chain can comprise or consist the amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist the amino acid sequence of SEQ ID NO: 362 and the second polypeptide chain can comprise or consist the amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist the amino acid sequence of SEQ ID NO: 362 and the second polypeptide chain can comprise or consist the amino acid sequence of SEQ ID NO: 333. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 363 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID No. 363 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 363 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 333. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 325 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 325 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 333. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 325 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 286 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 286 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 286, and the second polypeptide can comprise or consist of an amino acid sequence of SEW ID NO: 333. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 579 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 579 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 579 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 233. For example, the fusion protein can comprise or consist of SEQ ID NO: 581 and the second polypeptide chain can comprise or consist of SEQ ID NO.: 263. For example, the fusion protein can comprise or consist of SEQ ID NO: 581 and the second polypeptide chain can comprise or consist of SEQ ID NO.: 264. For example, the fusion protein can comprise or consist of SEQ ID NO: 581 and the second polypeptide chain can comprise or consist of SEQ ID NO.: 333. For example, the fusion protein can comprise or consist of SEQ ID NO: 582 and the second polypeptide chain can comprise or consist of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of SEQ ID NO: 582 and the second polypeptide chain can comprise or consist of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of SEQ ID NO: 582 and the second polypeptide chain can comprise or consist of SEQ ID NO: 333.

As described herein targeting is accomplished through the action of a blocking polypeptide moiety that also binds to a desired target, or through a targeting domain. The domain that recognizes a target antigen on a preferred target (for example a tumor-specific antigen), may be attached to the cytokine via a cleavable or non-cleavable linker. If attached by a non-cleavable linker, the targeting domain may further aid in retaining the cytokine in the tumor, and it may be considered a retention domain. The targeting domain does not necessarily need to be directly linked to the payload molecule, and it may be linked directly to another element of the fusion protein. This is especially true if the targeting domain is attached via a cleavable linker.

In one aspect is provided a fusion polypeptide comprising a cytokine polypeptide, or functional fragment, a mutein thereof, a functional variant thereof or a subunit thereof, and a blocking moiety, e.g. a steric blocking domain. The blocking moiety is fused to the cytokine polypeptide, directly or through a linker, and can be separated from the cytokine polypeptide by cleavage (e.g., protease mediated cleavage) of the fusion polypeptide at or near the fusion site or linker or in the blocking moiety. For example, when the cytokine polypeptide is fused to a blocking moiety through a linker that contains a protease cleavage site, the cytokine polypeptide is released from the blocking moiety and can bind its receptor, upon protease mediated cleavage of the linker. The linker is designed to be cleaved at the site of desired cytokine activity, for example in the tumor microenvironment, avoiding off-target cytokine activity and reducing overall toxicity of cytokine therapy.

The blocking moiety can also function as a serum half-life extension element. In some embodiments, the fusion polypeptide further comprises a separate serum half-life extension element. In some embodiments, the fusion polypeptide further comprises a targeting domain. In various embodiments, the serum half-life extension element is a water-soluble polypeptide such as optionally branched or multi-armed polyethylene glycol (PEG), full length human serum albumin (HSA) or a fragment that preserves binding to FcRn, an Fc fragment, or a nanobody that binds to FcRn directly or to human serum albumin.

In addition to serum half-life extension elements, the pharmaceutical compositions described herein preferably comprise at least one, or more targeting domains that bind to one or more target antigens or one or more regions on a single target antigen. It is contemplated herein that a polypeptide construct of the invention is cleaved, for example, in a disease-specific microenvironment or in the blood of a subject at the protease cleavage site and that the targeting domain(s) will bind to a target antigen on a target cell. At least one target antigen is involved in and/or associated with a disease, disorder or condition. Exemplary target antigens include those associated with a proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, a graft-versus-host disease or a host-versus-graft disease.

In some embodiments, a target antigen is a cell surface molecule such as a protein, lipid or polysaccharide. In some embodiments, a target antigen is a on a tumor cell, virally infected cell, bacterially infected cell, damaged red blood cell, arterial plaque cell, or fibrotic tissue cell.

Target antigens, in some cases, are expressed on the surface of a diseased cell or tissue, for example a tumor or a cancer cell. Target antigens for tumors include but are not limited to Fibroblast activation protein alpha (FAPa), Trophoblast glycoprotein (5T4), Tumor-associated calcium signal transducer 2 (Trop2), Fibronectin EDB (EDB-FN), fibronectin EIIIB domain, CGS-2, EpCAM, EGFR, HER-2, HER-3, c-Met, FOLR1, FAP, and CEA. Pharmaceutical compositions disclosed herein, also include proteins comprising two antigen binding domains that bind to two different target antigens known to be expressed on a diseased cell or tissue. Exemplary pairs of antigen binding domains include but are not limited to EGFR/CEA, EpCAM/CEA, and HER-2/HER-3.

In some embodiments, the targeting polypeptides independently comprise a scFv, a VH domain, a VL domain, a non-Ig domain, or a ligand that specifically binds to the target antigen. In some embodiments, the targeting polypeptides specifically bind to a cell surface molecule. In some embodiments, the targeting polypeptides specifically bind to a tumor antigen. In some embodiments, the targeting polypeptides specifically and independently bind to a tumor antigen selected from at least one of EpCAM, EGFR, HER-2, HER-3, cMet, CEA, and FOLR1. In some embodiments, the targeting polypeptides specifically and independently bind to two different antigens, wherein at least one of the antigens is a tumor antigen selected from EpCAM, EGFR, HER-2, HER-3, cMet, CEA, and FOLR1. In some embodiments, the targeting polypeptide serves as a retention domain and is attached to the cytokine via a non-cleavable linker.

As described herein, the cytokine blocking moiety can bind to the cytokine and thereby block activation of the cognate receptor of the cytokine.

This disclosure also related to nucleic acids, e.g., DNA, RNA, mRNA, that encode the conditionally active proteins described herein, as well as vectors and host cells that contain such nucleic acids.

This disclosure also relates to pharmaceutical compositions that contain a conditionally active protein, nucleic acid that encodes the conditionally active protein, and vectors and host cells that contain such nucleic acids. Typically, the pharmaceutical composition contains one or more physiologically acceptable carriers and/or excipients.

The disclosure also relates to therapeutic methods that include administering to a subject in need thereof an effective amount of a conditionally active protein, nucleic acid that encodes the conditionally active protein, vector or host cells that contain such a nucleic acid, and pharmaceutical compositions of any of the foregoing. Typically, the subject has, or is at risk of developing, a proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, a graft-versus-host disease or a host-versus-graft disease.

The disclosure also relates to the use of a conditionally active protein, nucleic acid that encodes the conditionally active protein, vector or host cells that contain such a nucleic acid, and pharmaceutical compositions of any of the foregoing, for treating a subject in need thereof. Typically, the subject has, or is at risk of developing, a proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, a graft-versus-host disease or a host-versus-graft disease.

The disclosure also relates to the use of a conditionally active protein, nucleic acid that encodes the conditionally active protein, vector or host cells that contain such a nucleic acid for the manufacture of a medicament for treating a disease, such as a proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, a graft-versus-host disease or a host-versus-graft disease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1E are a series of graphs showing activity of IL-2 fusion proteins in a HEKBlue IL-2 reporter assay in the presence of HSA. Squares depict activity of the uncut IL-2 polypeptide (intact) and triangles depict the activity of the cut polypeptide (cleaved). Circles depict activity of control IL-2. EC50 for each IL-12. EC50 values for each are shown in the table. FIGS. 1A-IE also depict results of the protein cleavage assay for each IL-2 polypeptide. Constructs tested and depicted include WW0475 (FIG. 1A), WW0517 (FIG. 1B), WW0548/556 (FIG. 1C), WW0735/523 (FIG. 1D), and WW0621/523 (FIG. 1E). FIG. 1F is a graph showing activity of a non-cleavable control, WW0729/523. FIG. 1F also depicts results of a protein cleavage assay for the non-cleavable control.

FIGS. 2A-2L are a series of graphs showing activity of fusion proteins in an IL-2 luciferase reporter assay. Closed squares depict activity of the uncut IL-2 polypeptide (intact) and open squares depict the activity of the cut IL-2 polypeptide (cleaved). Circles depict activity of the control (human IL-2). EC50 values for each are shown in the table (human IL-2). EC50 values for each are shown in the table. Constructs tested and depicted include WW0521/WW0556 (FIG. 2A), WW0521/WW0524 (FIG. 2B), WW0521/WW0523 (FIG. 2C), WW0520/WW0524 (FIG. 2D), WW0517 (FIG. 2E), WW0516 (FIG. 2F), WW0417 (FIG. 2G), WW0317 (FIG. 2H), WW0317 (FIG. 2I), and WW0520/WW0523 (FIG. 2J), WW0621/WW0523 (FIG. 2K), WW0048 (FIG. 2L).

FIGS. 3A-3J are a series of graphs showing activity of fusion proteins in an IL-2 T-Blast assay. In FIGS. 3B, 3D, 3J squares and in FIGS. 3A, 3C, 3E, 3I triangles depict activity of the uncut IL-2 polypeptide (intact), and in FIGS. 3B, 3D, 3J triangles, and in FIGS. 3A, 3C and 3E-3I upside down triangles depict the activity of the cut polypeptide (cleaved). Circles (FIGS. 3B, 3D, 3J) or squares (FIGS. 3A, 3C, 3E-3I) depict activity of the control human IL-2. EC50 values for each are shown in the table. Constructs tests and depicted include WW0317 (FIG. 3A), WW0516 (FIG. 3B), WW0354 (FIG. 3C), WW0517 (FIG. 3D), WW0621/0523 (FIG. 3E), WW0521/524 (FIG. 3F), WW0520/0523 (FIG. 3G), WW0729/523 (FIG. 3H), and WW0735/523 (FIG. 3I), WW0520/524 (FIG. 3J).

FIGS. 4A-4G are graphs that show results of analyzing WW0475, WW0520/0523, WW0548/0524, WW0548/0556, WW0517, WW0621/0523, and WW0619 IL-2 fusion proteins in a syngeneic MC38 mouse tumor model. Each graph shows average tumor volume (Mean+/−SEM) over time in mice treated with different doses of each of the fusion proteins as indicated. The data show tumor volume decreasing over time in a dose-dependent manner.

FIGS. 5A-5C are a series of spider plots showing activity of fusion proteins in the MC38 mouse syngeneic model corresponding to the data shown in FIG. 4A-4G. Each line in the plots is the tumor volume over time for a single mouse. FIG. 5A contains the data corresponding to vehicle treatment and fusion proteins WW0517 and WW0520/523. FIG. 5B contains the data corresponding to treatment with fusion proteins WW0548/0524, WW0548/0556, and WW0475. FIG. 5C contains the data corresponding to treatment with fusion proteins WW0619 and WW0621/0523.

FIGS. 6A-6C are a series of spider plots showing the impact of fusion proteins on body weight in an MC38 mouse syngeneic model corresponding to the data shown in FIGS. 5A-5C. Each line in the plots is the body weight over time for a single mouse. FIG. 6A contains the data corresponding to vehicle treatment and fusion proteins WW0517 and WW0520/523. FIG. 6B contains the data corresponding to treatment with fusion proteins WW0548/0524, WW0548/0556, and WW0475. FIG. 6C contains the data corresponding to treatment with fusion proteins WW0619 and WW0621/0523.

FIGS. 7A-7Q are a series of graphs showing activity of fusion proteins in an HEKBlue IL-12 reporter assay. FIGS. 7A-7Q depict IL-12/STAT4 activation in a comparison of human p40/murine p35 IL-12 or human IL-12 fusion proteins to chimeric IL-12 (mouse p35/human p⁴⁰) or recombinant human IL-12 (control). Squares depict activity of the uncut IL-12 polypeptide (intact) and triangles depict the activity of the cut IL-12 polypeptide (cleaved). Circles depict activity of the control. EC50 values for each are shown in the table.

FIGS. 8A-8D are a series of graphs showing activity of fusion proteins in an IL12 T-Blast assay. FIGS. 8A-8D depicts activation of IL-12 signaling in a comparison of a human p40/murine p35 IL12 or human IL12 fusion protein to control, chimeric IL-12 (human p40/murine p35 IL12) or recombinant human IL12. Squares depict activity of the uncut IL-12 polypeptide (intact) and triangles depict the activity of the cut IL-12 polypeptide (cleaved). Circles depict activity of the control chimeric IL-12 or recombinant human IL-12. EC50 values for each are shown in the table.

FIGS. 9A-9C are a series of graphs showing activity of fusion proteins in an IL-12 luciferase reporter assay. FIGS. 9A-9B depict activation of IL-12 signaling in a comparison of a human p40/murine p35 IL-12 fusion protein to recombinant human IL-12 (control). FIG. 9C depicts activation of IL-12 signaling in comparison of a human IL-12 (human p40/human p35 IL-12) fusion protein to recombinant human IL12. Closed squares depict activity of the uncut IL-12 polypeptide (intact) and open squares depict the activity of the cut polypeptide (cleaved). Circles depict activity of the control. EC50 values for each are shown in the table.

FIGS. 10A-10J are a series of graphs showing activity of fusion proteins in the B16-Blue IFN-α/β reporter assay. FIGS. 10A-10J depict activation of the IFN-α/β pathway in a comparison of mouse IFNα fusion protein to mouse IFNα (control). Squares depict activity of the uncut IFNα polypeptide (intact) and triangles depict the activity of the cut IFNα polypeptide (cleaved). Circles depict activity of the control (mouse IFNα). EC50 values for each are shown in the table. FIGS. 10A-10J also depict results of the protein cleavage assay for each IFNα fusion protein. Each IFNα fusion protein was run on an SDS-PAGE gel in both cleaved and uncleaved form. As can be seen in the gel, cleavage was complete.

FIGS. 11A-11B are graphs depicting results from a HEK-Blue IL-12 reporter assay performed on human p40/murine p35 IL12 fusion proteins before and after protease cleavage. Constructs ACP35 (FIG. 11A) and ACP34 (FIG. 11B) were tested. Analysis was performed based on quantification of Secreted Alkaline Phosphatase (SEAP) activity using the reagent QUANTI-Blue® (InvivoGen). Results confirm that IL12 protein fusion proteins are active.

FIGS. 12A-12F show a series of graphs depicting the results of HEK-blue assay of four IL-12 fusion proteins, before and after cleavage by MMP9. Analysis was performed based on quantification of Secreted Alkaline Phosphatase (SEAP) activity using the reagent QUANTI-Blue (InvivoGen). The data show greater activity in the cleaved IL12 than in the full fusion protein. Constructs tested were ACP06 (FIG. 12A), ACP07 (FIG. 12C), ACP08 (FIG. 12B), ACP09 (FIG. 12D), ACP10 (FIG. 12E), ACP11 (FIG. 12F).

FIG. 13 shows results of protein cleavage assay. Fusion protein ACP11 was run on an SDS-PAGE gel in both cleaved and uncleaved form. As can be seen in the gel, cleavage was complete.

FIG. 14 is a schematic which depicts a non-limiting example of an inducible cytokine protein, wherein the construct is activated upon protease cleavage of a linker attached between two subunits of the cytokine.

FIGS. 15A-15D are graphs depicting results from a HEK-Blue assay performed on human p40/murine p35 IL12 fusion proteins before and after protease cleavage. Results confirm that IL12 protein fusion proteins are active. Each proliferation assay was performed with HSA or without HSA.

FIGS. 16A-16F are a series of graphs showing activity of exemplary IFNγ fusion proteins compared to activity of mouse IFNγ control using WEHI 279 cell survival assay. Each assay was performed with medium containing HSA (+HSA) or not containing HSA (-HSA). Each fusion protein comprises an anti-HSA binder, and both uncleaved and MMP9 protease cleaved versions of the fusion protein were used in each assay.

FIGS. 17A-17F are a series of graphs showing activity of exemplary IFNγ fusion proteins compared to activity of mouse IFNγ control using B16 reporter assay. Each assay was performed with medium containing HSA (+HSA) or not containing HSA (-HSA). Each fusion protein comprises an anti-HSA binder, and both uncleaved and MMP9 protease cleaved versions of the fusion protein were used in each assay.

FIGS. 18A-18B show results of protein cleavage assay, as described in Example 2. Two constructs, ACP31 (IFN-α fusion protein; FIG. 18A) and ACP55 (IFN-γ fusion protein; 18B), were run on an SDS-PAGE gel in both cleaved and uncleaved form. As can be seen in the gel, cleavage was complete.

FIGS. 19A-19B are a series of graphs (FIGS. 19A and 19B) showing activity of exemplary IFNγ fusion proteins before and after protease cleavage using B16 reporter assay. Each assay was performed with culture medium containing HSA, and each fusion protein comprises an anti-HSA binder. Both uncleaved and MMP9 protease cleaved versions of the fusion protein were used in each assay.

FIGS. 20A-20B are a series of graphs (FIG. 20A and FIG. 20B) showing activity of exemplary IFNα fusion proteins before and after cleavage using a B16 reporter assay. Each assay was performed with medium containing HSA, and each fusion protein comprises an anti-HSA binder. Both uncleaved and MMP9 protease cleaved versions of the fusion protein were used in each assay.

FIGS. 21A-21D are a series of graphs depicting the results of tumor growth studies using the MC38 cell line. FIG. 21A-C show the effect of IFNγ and IFNγ fusion proteins on tumor growth when injected intraperitoneally (IP) using different dosing levels and schedules (ug=micrograms, BID=twice daily, BIW=twice weekly, QW=weekly). FIG. 21D shows the effect of intratumoral (IT) injection of IFNγ and IL-2 on tumor growth.

FIGS. 22A-22B are a series of graphs showing activity of exemplary IFNγ fusion proteins (ACP51 (FIG. 22A), and ACP52 (FIG. 22B)) cleaved by MMP9 protease compared to activity of uncleaved fusion proteins using B16 reporter assay. Each fusion protein comprises an anti-HSA binder and a tumor targeting domain.

FIGS. 23A-23B are a series of graphs showing activity of exemplary IFNγ fusion proteins (ACP53 and ACP54) cleaved by MMP9 protease compared to activity of uncleaved fusion proteins using B16 reporter assay. Each fusion protein comprises IFNγ directly fused to albumin.

FIGS. 24A-24D are graphs depicting results from a HEK-Blue IL-2 reporter assay performed on IL-2 fusion proteins and recombinant human IL2 (Rec hIL-2). Analysis was performed based on quantification of Secreted Alkaline Phosphatase (SEAP) activity using the reagent QUANTI-Blue (InvivoGen). FIG. 24A shows results of IL-2 constructs ACP132 and ACP 133 with and without albumin. FIG. 24B shows results of IL-2 construct ACP16 cleaved and uncleaved. Results of a protein cleavage assay of ACP16 in cleaved and uncleaved forms is also depicted. FIG. 24C shows results of IL-2 construct ACP153 in cleaved and uncleaved forms. Results of a protein cleavage assay are also depicted. FIG. 24D illustrates the results from a HEK-Blue IL-2 assay using wild-type cytokine, intact fusion protein, and protease-cleaved fusion protein.

FIGS. 25A and 25B are two graphs showing analysis of ACP16 (FIG. 25A) and ACP124 (FIG. 25B) in a HEKBlue IL-2 reporter assay in the presence of HSA. Circles depict the activity of the uncut polypeptide; squares depict activity of the cut polypeptide. FIG. 25C is a graph showing results of a CTLL-2 proliferation assay. CTLL2 cells (ATCC) were plated in suspension at a concentration of 500,000 cells/well in culture media with or without 40 mg/ml human serum albumin (HSA) and stimulated with a dilution series of activatable hIL2 for 72 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved activatable ACP16 was tested. Cleaved activatable hIL2 was generated by incubation with active MMP9. Cell activity was assessed using a CellTiter-Glo (Promega) luminescence-based cell viability assay. Circles depict intact fusion protein, and squares depict protease-cleaved fusion protein.

FIGS. 26A-26C are a series of graphs showing activity of fusion proteins in an HEKBIue IL-12 reporter assay. FIG. 26A depicts IL-12/STAT4 activation in a comparison of ACP11 (a human p40/murine p35 IL12 fusion protein) to ACP04 (negative control). FIG. 26B is a graph showing analysis of ACP91 (a chimeric IL-12 fusion protein). Squares depict activity of the uncut ACP91 polypeptide, and triangles depict the activity of the cut polypeptide (ACP91+MMP9). EC50 values for each are shown in the table. FIG. 26C is a graph showing analysis of ACP136 (a chimeric IL-12 fusion protein). Squares depict activity of the uncut ACP136 polypeptide, and triangles depict the activity of the cut polypeptide (ACP136+MMP9). EC50 values for each are shown in the table insert.

FIGS. 27A-27F are a series of graphs showing that cleaved mouse IFNα1 polypeptides ACP31 (FIG. 27A), ACP125 (FIG. 27B), ACP126 (FIG. 27C), ACP127 (FIG. 27D), APC128 (FIG. 27E), and APC129 (FIG. 27F) are active in an B16-Blue IFN-α/p reporter assay.

FIGS. 28A-28N are a series of graphs depicting the activity of ACP56 (FIG. 28A), ACP57 (FIG. 28B) ACP58 (FIG. 28C), ACP59 (FIG. 28D), ACP60 (FIG. 28E), ACP61+HSA (FIG. 28F), ACP30+HSA (FIG. 28G), ACP73 (FIG. 28H), ACP70+HSA (FIG. 28I), ACP71 (FIG. 28J), ACP72 (FIG. 28K), ACP 73 (FIG. 28L), ACP74 (FIG. 28M), and ACP75 (FIG. 28N) in a B16 IFNγ reporter assay. Each fusion was tested for its activity when cut (squares) and uncut (circles).

FIGS. 29A-29B are two graphs showing results of analyzing ACP31 (mouse IFNα1 fusion protein) and ACP11 (a human p40/murine p35 IL12 fusion protein) in a tumor xenograft model. FIG. 29A shows tumor volume over time in mice treated with 33 μg ACP31 (circles), 110 μg ACP31 (triangles), 330 μg ACP31 (diamonds), and as controls 1p g murine wild type IFNα1 (dashed line, squares) and 10 μg mIFNα1 (dashed line, small circles). Vehicle alone is indicated by large open circles. The data show tumor volume decreasing over time in a dose-dependent manner in mice treated with ACP31. FIG. 29B shows tumor volume over time in mice treated with 17.5 μg ACP11 (squares), 175 μg ACP11 (triangles), 525 μg ACP11 (circles), and as controls 2 μg ACP04 (dashed line, triangles) and 10 μg ACP04 (dashed line, diamonds). Vehicle alone is indicated by large open circles. The data show tumor volume decreasing over time in a dose-dependent manner in mice treated with both ACP11 and ACP04 (a human p40/murine p35 IL12 fusion protein).

FIGS. 30A-30F are a series of spaghetti plots showing tumor volume over time in a mouse xenograft tumor model in mice each treated with vehicle alone (FIG. 30A), 2 μg ACP04 (FIG. 30B), 10 μg ACP04 (FIG. 30C), 17.5 μg ACP11 (FIG. 30D), 175 μg ACP11 (FIG. 30E), and 525 μg ACP11 (FIG. 30F). Each line represents a single mouse.

FIG. 31A-31C are three graphs showing results of analyzing ACP16 and ACP124 in a tumor xenograft model. FIG. 31A shows tumor volume over time in mice treated with 4.4 μg ACP16 (squares), 17 μg ACP16 (triangles), 70 μg ACP16 (downward triangles), 232 μg ACP16 (dark circles), and as a comparator 12 μg wild type IL-2 (dashed line, triangles) and 36 μg wild type IL-2 (dashed line, diamonds. Vehicle alone is indicated by large open circles. The data show tumor volume decreasing over time in a dose-dependent manner in mice treated with ACP16 at higher concentrations. FIG. 31B shows tumor volume over time in mice treated with 17 μg ACP124 (squares), 70 μg ACP124 (triangles), 230 μg ACP124 (downward triangles), and 700 μg ACP124. Vehicle alone is indicated by large open circles. FIG. 31C shows tumor volume over time in mice treated with 17 μg ACP16 (triangles), 70 μg ACP16 (circles), 232 μg ACP16 (dark circles), and as a comparator 17 μg ACP124 (dashed line, triangles) 70 μg ACP124 (dashed line, diamonds), 230 μg ACP124 (dashed line, stars). Vehicle alone is indicated by dark downward triangles. The data show tumor volume decreasing over time in a dose-dependent manner in mice treated with ACP16, but not ACP124.

FIG. 32A-32B are a series of spaghetti plots showing activity of fusion proteins in an MC38 mouse xenograft model corresponding to the data shown in FIG. 31A-31C. Each line in the plots is a single mouse.

FIG. 33 is a graph showing tumor volume over time in a mouse xenograft model showing tumor growth in control mice (open circles) and AP16-treated mice (squares).

FIGS. 34A-34D are a series of survival plots showing survival of mice over time after treatment with cleavable fusion proteins. FIG. 34A shows data for mice treated with vehicle alone (gray line), 17 μg ACP16 (dark line), and 17 μg ACP124 (dashed line). FIG. 34B shows data for mice treated with vehicle alone (gray line), 70 μg ACP16 (dark line), and 70 μg ACP124 (dashed line). FIG. 34C shows data for mice treated with vehicle alone (gray line), 232 μg ACP16 (dark line), and 230 μg ACP124 (dashed line). FIG. 34D shows data for mice treated with vehicle alone (gray line), 232 μg ACP16 (dark line), and 700 μg ACP124 (dashed line).

FIG. 35 a series of spaghetti plots showing activity of fusion proteins in an MC38 mouse xenograft model. All mouse groups were given four doses total except for the highest three doses of APC132, wherein fatal toxicity was detected after 1 week/2 doses. Shown are vehicle alone (top), 17, 55, 70, and 230 μg ACP16 (top full row), 9, 28, 36, and 119 μg ACP132 (middle full row), and 13, 42, 54, and 177 μg ACP21 (bottom full row). Each line in the plots represents an individual animal.

FIGS. 36A-36H are a series of graphs showing activity of fusion proteins in the HEK-Blue IFN-α/p reporter assay. FIGS. 36A-36H depict activation of the IFN-α/β pathway in a comparison of human IFNα fusion protein) to control (human IFNα). Squares depict activity of the uncut IFNα polypeptide (intact) and triangles depict the activity of the cut IFNα polypeptide (cleaved). Circles depict activity of the control (human IFNα). EC50 values for each are shown in the table. Results confirm that the IFNα fusion proteins are active and inducible. FIGS. 36A-36H also depict results of the protein cleavage assay for each IFNα fusion protein. Each IFNα fusion protein was run on an SDS-PAGE gel in both cleaved and uncleaved form. As can be seen in the gel, cleavage was complete.

FIGS. 37A-37D are a series of graphs showing activity of fusion proteins in the HEK-Blue IFN-α/p reporter assay. FIGS. 37A-37B depict activation of the IFN-α/β pathway in a comparison of a mouse IFNβ fusion protein to control (mouse IFNβ). FIGS. 37C-37D depict activation of the IFN-α/β pathway in a comparison of a human IFNβ fusion protein to control (human IFNβ). Squares depict activity of the uncut IFNβ polypeptide (intact) and triangles depict the activity of the cut IFNβ polypeptide (cleaved). Circles depict activity of the control. EC50 values for each are shown in the table. Results confirm that the IFNβ fusion proteins are active and inducible.

FIGS. 38A-38C are a series of graphs showing activity of fusion proteins in the human PBMCs assay. FIGS. 38A-38C depict activation of the IFNα pathway in a comparison of human IFNα fusion protein to control (human IFNα). Squares depict activity of the uncut IFNα polypeptide (intact) and triangles depict the activity of the cut IFNα polypeptide (cleaved). Circles depict activity of the control human IFNα. EC50 values for each are shown in the table. Analysis was performed based on quantification of CXCL-10 (IP-10). Results confirm that the IFNα fusion proteins are active and inducible.

FIGS. 39A-39G show are results of analyzing IFN fusion proteins in syngeneic MC38 mouse tumor model. FIG. 39A shows average tumor volume over time in mice treated with 369 μg WW0610 (square), 553 μg WW0610 (down triangle), 830 μg WW0610 (up triangle), and 1,245 μg WW0610 (circle). Vehicle alone is indicated by a black circle. FIG. 39B shows average tumor volume over time in mice treated with 1,231 μg WW0815 (square), 1,845 μg WW0815 (down triangle), 2,770 μg WW0815 (up triangle), and 4,154 μg WW0815 (circle). Vehicle alone is indicated by a black circle. FIG. 39C shows average tumor volume over time in mice treated with 4.6 μg WW0644 (square), 9.3 μg WW0644 (down triangle), 19 μg WW0644 (up triangle), and 37 μg WW0644 (circle). Vehicle alone is indicated by a black circle. FIG. 39D shows average tumor volume over time in mice treated with 31 μg WW0816 (square), 62 μg WW0816 (down triangle), 123 μg WW0816 (up triangle), and 247 μg WW0816 (circle). Vehicle alone is indicated by a black circle. FIG. 39E shows average tumor volume over time in mice treated with 110 μg WW0609 (square), 830 μg WW0609 (down triangle), and 1,320 μg WW0609 (up triangle). FIG. 39F shows average tumor volume over time in mice treated with 110 μg WW0610 (square), 830 μg WW0610 (down triangle), and 1,320 μg WW0610 (up triangle). FIG. 39G shows average tumor volume over time in mice treated with 0.3 μg WW0643 (square), 1.5 μg WW0643 (down triangle), 7.5 μg WW0643 (up triangle), and 37.5 μg WW0643 (diamond). Vehicle alone is indicated by a black circle.

FIG. 40A-40G shows a series of spider plots showing activity of fusion proteins in an MC38 xenograft model corresponding to data in FIGS. 39A-39G. Each line in the plots is the tumor volume over time for a single mouse.

FIG. 41A-41G show average percent body weight over time in mice treated with the IFN fusion proteins in FIGS. 39A-39G.

FIGS. 42A-42E shows the results of B16 IFN reporter assays. Inducible interferon constructs of interest were tested before and after cleavage. The relevant wildtype IFN was tested as a control.

FIG. 43 shows binding data of ACP16, ACP10, ACP11

FIGS. 44A-44D depict the activity of cytokine fusion proteins constructs ACP243, ACP244, ACP243, ACP244, and ACP247.

FIG. 45 shows a series of spider plots showing tumor volume over time during treatment with vehicle, IL-12, ACP11 or ACP10.

FIGS. 46A-46D, 47A-47D, 48A, 48B, 49A-49I, 50A, 50B, and 51A-51C shows data (tumor volume and/or body weight) for mice treated with cytokine fusion proteins constructs.

FIGS. 52A-52N, 53A, and 53B depict the activity of cytokine fusion proteins constructs.

FIG. 54A-54N shows the results of proliferation assays comparing cut protein, uncut protein, and IL2 as a control.

FIGS. 55A-55N shows the results of HekBlue IL2 reporter assays comparing activity of constructs with and without protease cleavage; IL-2 is included as a control.

FIGS. 56, 57A-57D, 58, 59A-59Z depict the activity of cytokine fusion proteins constructs.

FIGS. 60A-60G shows a series of spider plots showing the impact of IFN fusion proteins on body weight in an MC38 mouse xenograft model corresponding to the data shown in FIGS. 41A-41G. Each line in the plots is the body weight over time for a single mouse.

FIGS. 61A-61B are a series of graphs showing activity of fusion proteins in the B16-Blue IFN-α/β reporter assay. FIG. 61A depicts activation of the IFN-α/β pathway for construct WW0609 in the presence and absence of albumin. FIG. 61B depicts activation of the IFN-α/β pathway for construct WW0643 in the presence and absence of albumin. Squares depict activity of the uncut IFNα polypeptide (intact) and triangles depict the activity of the cut IFNα polypeptide (cleaved). Circles depict activity of the control (mouse IFNα). EC50 values for each are shown in the table.

DETAILED DESCRIPTION

Disclosed herein are methods and compositions to engineer and use constructs comprising inducible cytokines. Cytokines are potent immune agonists, which lead to them being considered promising therapeutic agents for oncology. However, cytokines proved to have a very narrow therapeutic window. Cytokines have short serum half-lives and are also considered to be highly potent. Consequently, therapeutic administration of cytokines produced undesirable systemic effects and toxicities. These were exacerbated by the need to administer large quantities of cytokine in order to achieve the desired levels of cytokine at the intended site of cytokine action (e.g., a tumor). Unfortunately, due to the biology of cytokines and inability to effectively target and control their activity, cytokines did not achieve the hoped-for clinical advantages in the treatment of tumors.

Disclosed herein are fusion proteins that overcome the toxicity and short half-life problems that have severely limited the clinical use of cytokines in oncology. The fusion proteins contain cytokine polypeptides that have receptor agonist activity. But in the context of the fusion protein, the cytokine receptor agonist activity is attenuated, and the circulating half-life is extended. The fusion proteins include protease cleave sites, which are cleaved by proteases that are associated with a desired site of cytokine activity (e.g., a tumor), and are typically enriched or selectively present at the site of desired activity. Thus, the fusion proteins are preferentially (or selectively) and efficiently cleaved at the desired site of activity to limit cytokine activity substantially to the desired site of activity, such as the tumor microenvironment. Protease cleavage at the desired site of activity, such as in a tumor microenvironment, releases a form of the cytokine from the fusion protein that is much more active as a cytokine receptor agonist than the fusion protein (typically at least about 100× more active than the fusion protein). The form of the cytokine that is released upon cleavage of the fusion protein typically has a short half-life, which is often substantially similar to the half-life of the naturally occurring cytokine, further restricting cytokine activity to the tumor microenvironment. Even though the half-life of the fusion protein is extended, toxicity is dramatically reduced or eliminated because the circulating fusion protein is attenuated, and active cytokine is targeted to the tumor microenvironment. The fusion proteins described herein, for the first time, enable the administration of an effective therapeutic dose of a cytokine to treat tumors with the activity of the cytokine substantially limited to the tumor microenvironment, and dramatically reduces or eliminates unwanted systemic effects and toxicity of the cytokine.

The fusion proteins disclosed herein typically comprise a cytokine polypeptide [A], a blocking moiety [D], optionally a half-life extension moiety [H], and a protease-cleavable polypeptide linker. The cytokine polypeptide and the blocking moiety and the optional half-life extension element when present are operably linked by the protease-cleavable polypeptide linker and the fusion polypeptide has attenuated cytokine receptor activating activity, e.g., the cytokine-receptor activating activity of the fusion polypeptide is at least about 10× less than the cytokine receptor activating activity of the polypeptide that contains the cytokine polypeptide that is produced by cleavage of the protease cleavable linker. Some preferred fusion polypeptides are of one of formula (I)-(VI):

[A]-[L1]-[H]-[L2]-[D]  (I);

[D]-[L2]-[H]-[L1]-[A]  (II);

[A]-[L1]-[D]-[L2]-[H]  (III);

[H]-[L2]-[D]-[L1]-[A]  (IV);

[H]-[L1]-[A]-[L2′]-[D]  (V);

[D]-[L1]-[A]-[L2′]-[H]  (VI);

wherein [A] is a cytokine polypeptide, [D] is a blocking moiety, [H] is a half-life extension moiety, [L1] is a protease-cleavable polypeptide linker, [L2] is an polypeptide linker that is optionally protease-cleavable, and [L2′] is a protease-cleavable polypeptide linker. [L1] and [L2] or [L1] and [L2′] can be have the same or different amino acid sequence and or protease-cleavage site (when L2 is protease-cleavable) as desired.

This disclosure further relates to pharmaceutical compositions that contain the inducible fusion protein and an additional therapeutic agent, as well as nucleic acids that encode the polypeptides, and recombinant expression vectors and host sells for making such fusion proteins. Also provided herein are methods of using the disclosed fusion proteins in the treatment of diseases, conditions, and disorders.

Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

“Cytokine” is a well-known term of art that refers to any of a class of immunoregulatory proteins (such as interleukin or interferon) that are secreted by cells especially of the immune system and that are modulators of the immune system. Cytokine polypeptides that can be used in the fusion proteins disclosed herein include, but are not limited to transforming growth factors, such as TGF-α and TGF-β (e.g., TGFbeta1, TGFbeta2, TGFbeta3); interferons, such as interferon-α, interferon-β, interferon-γ, interferon-kappa and interferon-omega; interleukins, such as IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21 and IL-25; tumor necrosis factors, such as tumor necrosis factor alpha and lymphotoxin; chemokines (e.g., C-X-C motifchemokine 10 (CXCL10), CCL19, CCL20, CCL21), and granulocyte macrophage-colony stimulating factor (GM-CS), as well as fragments of such polypeptides that active the cognate receptors for the cytokine (i.e., functional fragments of the foregoing). “Chemokine” is a term of art that refers to any of a family of small cytokines with the ability to induce directed chemotaxis in nearby responsive cells.

Cytokines are well-known to have short serum half-lives that frequently are only a few minutes or hours. Even forms of cytokines that have altered amino acid sequences intended to extend the serum half-life yet retain receptor agonist activity typically also have short serum half-lives. As used herein, a “short-half-life cytokine” refers to a cytokine that has a substantially brief half-life circulating in the serum of a subject, such as a serum half-life that is less than 10, less than 15, less than 30, less than 60, less than 90, less than 120, less than 240, or less than 480 minutes. As used herein, a short half-life cytokine includes cytokines which have not been modified in their sequence to achieve a longer than usual half-life in the body of a subject and polypeptides that have altered amino acid sequences intended to extend the serum half-life yet retain receptor agonist activity. This latter case is not meant to include the addition of heterologous protein domains, such as a bona fide half-life extension element, such as serum albumin.

“Sortases” are transpeptidases that modify proteins by recognizing and cleaving a carboxyl-terminal sorting signal embedded in or terminally attached to a target protein or peptide. Sortase A catalyzes the cleavage of the LPXTG motif (SEQ ID NO.: 442) (where X is any standard amino acid) between the Thr and Gly residue on the target protein, with transient attachment of the Thr residue to the active site Cys residue on the enzyme, forming an enzyme-thioacyl intermediate. To complete transpeptidation and create the peptide-monomer conjugate, a biomolecule with an N-terminal nucleophilic group, typically an oligoglycine motif, attacks the intermediate, displacing Sortase A and joining the two molecules.

As used herein, the term “steric blocker” refers to a polypeptide or polypeptide moiety that can be covalently bonded to a cytokine polypeptide directly or indirectly through other moieties such as linkers, for example in the form of a chimeric polypeptide (fusion protein), but otherwise does not covalently bond to the cytokine polypeptide. A steric blocker can non-covalently bond to the cytokine polypeptide, for example though electrostatic, hydrophobic, ionic or hydrogen bonding. A steric blocker typically inhibits or blocks the activity of the cytokine moiety due to its proximity to the cytokine moiety and comparative size. A steric blocker may also block by virtue of recruitment of a large protein binding partner. An example of this is an antibody which binds to serum albumin; while the antibody itself may or may not be large enough to block activation or binding on its own, recruitment of albumin allows for sufficient steric blocking.

As used and described herein, a “half-life extension element” is a part of the chimeric polypeptide that increases the serum half-life and improve pK, for example, by altering its size (e.g., to be above the kidney filtration cutoff), shape, hydrodynamic radius, charge, or parameters of absorption, biodistribution, metabolism, and elimination.

As used herein, the terms “activatable,” “activate,” “induce,” and “inducible” refer to the ability of a protein, i.e. a cytokine, that is part of a fusion protein, to bind its receptor and effectuate activity upon cleavage of additional elements from the fusion protein.

As used herein, “plasmids” or “viral vectors” are agents that transport the disclosed nucleic acids into the cell without degradation and include a promoter yielding expression of the nucleic acid molecule and/or polypeptide in the cells into which it is delivered.

As used herein, the terms “peptide”, “polypeptide”, or “protein” are used broadly to mean two or more amino acids linked by a peptide bond. Protein, peptide, and polypeptide are also used herein interchangeably to refer to amino acid sequences. It should be recognized that the term polypeptide is not used herein to suggest a particular size or number of amino acids comprising the molecule and that a peptide of the invention can contain up to several amino acid residues or more.

As used throughout, “subject” can be a vertebrate, more specifically a mammal (e.g. a human, horse, cat, dog, cow, pig, sheep, goat, mouse, rabbit, rat, and guinea pig), birds, reptiles, amphibians, fish, and any other animal. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.

As used herein, “patient” or “subject” may be used interchangeably and can refer to a subject with a disease or disorder (e.g. cancer). The term patient or subject includes human and veterinary subjects.

As used herein the terms “treatment”, “treat”, or “treating” refers to a method of reducing the effects of a disease or condition or symptom of the disease or condition. Thus, in the disclosed method, treatment can refer to at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or substantially complete reduction in the severity of an established disease or condition or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition.

As used herein, the terms “prevent”, “preventing”, and “prevention” of a disease or disorder refers to an action, for example, administration of the chimeric polypeptide or nucleic acid sequence encoding the chimeric polypeptide, that occurs before or at about the same time a subject begins to show one or more symptoms of the disease or disorder, which inhibits or delays onset or exacerbation of one or more symptoms of the disease or disorder.

As used herein, references to “decreasing”, “reducing”, or “inhibiting” include a change of at least about 10%, of at least about 20%, of at least about 30%, of at least about 40%, of at least about 50%, of at least about 60%, of at least about 70%, of at least about 80%, of at least about 90% or greater as compared to a suitable control level. Such terms can include but do not necessarily include complete elimination of a function or property, such as agonist activity.

An “attenuated cytokine receptor agonist” is a cytokine receptor agonist that has decreased receptor agonist activity as compared to the cytokine receptor's naturally occurring agonist. An attenuated cytokine agonist may have at least about 10×, at least about 50×, at least about 100×, at least about 250×, at least about 500×, at least about 1000× or less agonist activity as compared to the receptor's naturally occurring agonist. When a fusion protein that contains a cytokine polypeptide as described herein is described as “attenuated” or having “attenuated activity”, it is meant that the fusion protein is an attenuated cytokine receptor agonist.

An “intact fusion protein” is a fusion protein in which no domain has been removed, for example by protease cleavage. A domain may be removable by protease cleavage or other enzymatic activity, but when the fusion protein is “intact”, this has not occurred.

As used herein “moiety” refers to a portion of a molecule that has a distinct function within that molecule, and that function may be performed by that moiety in the context of another molecule. A moiety may be a chemical entity with a particular function, or a portion of a biological molecule with a particular function. For example, a “blocking moiety” within a fusion protein is a portion of the fusion protein which is capable of blocking the activity of some or all of the fusion polypeptide. This may be a protein domain, such as serum albumin. Blocking may be accomplished by a steric blocker or a specific blocker. A steric blocker blocks by virtue of size and position and not based upon specific binding; an examples is serum albumin. A specific blocker blocks by virtue of specific interactions with the moiety to be blocked. A specific blocker must be tailored to the particular cytokine or active domain; a steric blocker can be used regardless of the payload, as long as it is large enough. If desired a blocking moiety that is incorporated into a fusion proteins described herein can associate with another polypeptide to create a specific binding domain. For example, if a cytokine binding fragment of an antibody is used as the blocking moiety, the fusion polypeptide can include an scFv that is specific for the cytokine as the blocking moiety or the fusion polypeptide can comprise half of a Fab, for example VH-CH1 or VL-CL as the blocking moity, which can associate with a complementary chain VL-CL or VH-CH1, respectively, to form an Fab fragment that specifically binds the cytokine. As further described herein, the blocking moiety may block activity of the fusion protein directly or when the blocking moiety associates with another polypeptide. For example, when an anti-HSA scFv binds HSA or when a VH-CH1 polypeptide associates with a complementary VL-CL polypeptide and then binds the cytokine polypeptide.

In general, the therapeutic use of cytokines is strongly limited by their systemic toxicity. TNF, for example, was originally discovered for its capacity of inducing the hemorrhagic necrosis of some tumors, and for its in vitro cytotoxic effect on different tumoral lines, but it subsequently proved to have strong pro-inflammatory activity, which can, in case of overproduction conditions, dangerously affect the human body. As the systemic toxicity is a fundamental problem with the use of pharmacologically active amounts of cytokines in humans, novel derivatives and therapeutic strategies are now under evaluation, aimed at reducing the toxic effects of this class of biological effectors while keeping their therapeutic efficacy.

IL-2 exerts both stimulatory and regulatory functions in the immune system and is, along with other members of the common γ chain (γc) cytokine family, central to immune homeostasis. IL-2 mediates its action by binding to IL-2 receptors (IL-2R), consisting of either trimeric receptors made of IL-2Rα (CD25), IL-2Rβ (CD122), and IL-2Rγ (γc, CD132) chains or dimeric βγ IL-2Rs (1, 3). Both IL-2R variants are able to transmit signal upon IL-2 binding. However, trimeric αβγ IL-2Rs have a roughly 10-100 times higher affinity for IL-2 than dimeric βγ IL-2Rs (3), implicating that CD25 confers high-affinity binding of IL-2 to its receptor but is not crucial for signal transduction. Trimeric IL-2Rs are found on activated T cells and CD4+ forkhead box P3 (FoxP3)+ T regulatory cells (Treg), which are sensitive to IL-2 in vitro and in vivo. Conversely, antigen-experienced (memory) CD8+, CD44 high memory-phenotype (MP) CD8+, and natural killer (NK) cells are endowed with high levels of dimeric βγ IL-2Rs, and these cells also respond vigorously to IL-2 in vitro and in vivo.

Expression of the high-affinity IL-2R is critical for endowing T cells to respond to low concentrations of IL-2 that is transiently available in vivo. IL-2Rα expression is absent on naive and memory T cells but is induced after antigen activation. IL-2Rβ is constitutively expressed by NK, NKT, and memory CD8+ T cells but is also induced on naive T cells after antigen activation. γc is much less stringently regulated and is constitutively expressed by all lymphoid cells. Once the high-affinity IL-2R is induced by antigen, IL-2R signaling upregulates the expression of IL-2Rα in part through Stat5-dependent regulation of Il2ra transcription (Kim et al., 2001). This process represents a mechanism to maintain expression of the high-affinity IL-2R and sustain IL-2 signaling while there remains a source of IL-2.

IL-2 is captured by IL-2Rα through a large hydrophobic binding surface surrounded by a polar periphery that results in a relatively weak interaction (Kd 10-8 M) with rapid on-off binding kinetics. However, the IL-2Rα-IL-2 binary complex leads to a very small conformational change in IL-2 that promotes association with IL-2Rβ through a distinct polar interaction between IL-2 and IL-2Rβ. The pseudo-high affinity of the IL2/α/β trimeric complex (i.e. Kd ˜300 μM) clearly indicates that the trimeric complex is more stable than either IL2 bound to the α chain alone (Kd=10 nM) or to the 0 chain alone (Kd=450 nM) as shown by Ciardelli's data. In any event, the IL2/α/β trimer then recruits the γ chain into the quaternary complex capable of signaling, which is facilitated by the large composite binding site on the IL2-bound β chain for the γ chain.

In other words, the ternary IL-2Rα-IL-2Rβ-IL-2 complex then recruits γc through a weak interaction with IL-2 and a stronger interaction with IL-2Rβ to produce a stable quaternary high-affinity IL-2R (Kd 10-11 M which is 10 pM). The formation of the high-affinity quaternary IL-2-IL-2R complex leads to signal transduction through the tyrosine kinases Jak1 and Jak3, which are associated with IL-2Rβ and γc, respectively (Nelson and Willerford, 1998). The quaternary IL-2-IL-2R complex is rapidly internalized, where IL-2, IL-2Rβ, and γc are rapidly degraded, but IL-2Rα is recycled to the cell surface (Hémar et al., 1995; Yu and Malek, 2001). Thus, those functional activities that require sustained IL-2R signaling require a continued source of IL-2 to engage IL-2Rα and form additional IL-2-IL-2R signaling complexes.

Interleukin-15 (IL-15), another member of the 4-alpha-helix bundle family of cytokines, has also emerged as an immunomodulator for the treatment of cancer. IL-15 is initially captured via IL-15Rα, which is expressed on antigen-presenting dendritic cells, monocytes and macrophages. IL-15 exhibits broad activity and induces the differentiation and proliferation of T, B and natural killer (NK) cells via signaling through the IL-15/IL-2-R-β (CD122) and the common γ chain (CD132). It also enhances cytolytic activity of CD8⁺ T cells and induces long-lasting antigen-experienced CD8⁺CD44 memory T cells. IL-15 stimulates differentiation and immunoglobulin synthesis by B cells and induces maturation of dendritic cells. It does not stimulate immunosuppressive T regulatory cells (Tregs). Thus, boosting IL-15 activity selectively in the tumor micro-environment could enhance innate and specific immunity and fight tumors (Waldmann et al., 2012). IL-15 was initially identified for its ability to stimulate T cell proliferation in an IL-2-like manner through common receptor components (IL-2R/15Rβ-γc) and signaling through JAK1/JAK3 and STAT3/STAT5. Like IL-2, IL-15 has been shown to stimulate proliferation of activated CD4−CD8−, CD4+CD8+, CD4+ and CD8+ T cells as well as facilitate the induction of cytotoxic T-lymphocytes, and the generation, proliferation and activation of NK cells (Waldmann et al., 1999). However, unlike IL-2 which is required to maintain forkhead box P3 (FOXP3)-expressing CD4+CD25+ Treg cells and for the retention of these cells in the periphery, IL-15 has little effect on Tregs (Berger et al., 2009). This is important as FOXP3-expressing CD4+CD25+ Tregs inhibit effector T cells, thereby inhibiting immune responses including those directed against the tumor. IL-2 also has a crucial role in initiating activation induced cell death (AICD), a process that leads to the elimination of self-reactive T cells, whereas IL-15 is an anti-apoptotic factor for T cells (Marks-Konczalik et al., 2000). IL-15 co-delivered with HIV peptide vaccines has been shown to overcome CD4+ T cell deficiency by promoting longevity of antigen-specific CD8+ T cells and blocking TRAIL-mediated apoptosis (Oh et al., 2008). Furthermore, IL-15 promotes the long-term maintenance of CD8+CD44hi memory T cells (Kanegane et al., 1996).

The importance of IL-15 and IL-15Rα to T and NK cell development is further highlighted by the phenotype of IL-15Rα^(+/+) and IL-15^(−/−) mice. Knockout mice demonstrate decreased numbers of total CD8+ T cells, and are deficient in memory-phenotype CD8+ T cells, NK cells, NK/T cells and some subsets of intestinal intraepithelial lymphocytes, indicating that IL-15 provides essential positive homeostatic functions for these subsets of cells (Lodolce et al., 1996; Kennedy et al., 1998). The similarities in the phenotypes of these two strains of knockout mice suggest the importance of IL-15Rα in maintaining physiologically relevant IL-15 signals.

IL-15 is presented in trans by the IL-15 receptor alpha-chain to the IL-15Rβγc complex displayed on the surface of T cells and natural killer (NK) cells (Han et al., 2011). The IL-15Ra-chain plays a role of chaperone protein, stabilizes, and increases IL-15 activity (Desbois et al., 2016). It has been shown that exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Ra frequently downregulated in cancer patients. Therefore, the fusion protein RLI, composed of the sushi+ domain of IL15Ra coupled via a linker to IL-15, has been suggested as an alternative approach to IL15 therapy (Bessard et al., 2009). It was found that administration of soluble IL-15/IL-15Rα complexes greatly enhanced IL-15 serum half-life and bioavailability in vivo (Stoklasek et al., 2010).

In addition to the effects on T and NK cells, IL-15 also has several effects on other components of the immune system. IL-15 protects neutrophils from apoptosis, modulates phagocytosis and stimulates the secretion of IL-8 and IL-1R antagonist. It functions through the activation of JAK2, p38 and ERK1/2 MAPK, Syk kinase and the NF-kB transcriptional factor (Pelletier et al., 2002). In mast cells, IL-15 can act as a growth factor and an inhibitor of apoptosis. In these cells IL-15 activates the JAK2/STAT5 pathway without the requirement of γc binding (Tagaya et al., 1996). IL-15 also induces B lymphocyte proliferation and differentiation, and increases immunoglobulin secretion (Armitage et al., 1995). It also prevents Fas-mediated apoptosis and allows induction of antibody responses partially independent of CD4-help (Demerci et al., 2004; Steel et al., 2010). Monocytes, macrophages and dendritic cells effectively transcribe and translate IL-15. They also respond to IL-15 stimulation. Macrophages respond by increasing phagocytosis, inducing IL-8, IL-12 and MCP-1 expression, and secreting IL-6, IL-8 and TNF α (Budagian et al., 2006). Dendritic cells incubated with IL-15 demonstrate maturation with increased CD83, CD86, CD40, and MHC class II expression, are also resistant to apoptosis, and show enhanced interferon-γ secretion (Anguille et al., 2009).

IL-15 has also been shown to have effects on non-hematological cells including myocytes, adipocytes, endothelial and neural cells. IL-15 has an anabolic effect on muscle and may support muscle cell differentiation (Quinn et al., 1995). It stimulates myocytes and muscle fibers to accumulate contractile protein and is able to slow muscle wasting in rats with cancer-related cachexia (Figueras et al., 2004). IL-15 has also been shown to stimulate angiogenesis (Angiolillo et al., 1997) and induce microglial growth and survival (Hanisch et al., 1997).

Interleukin-7 (IL-7), also of the IL-2/IL-15 family, is a well-characterized pleiotropic cytokine, and is expressed by stromal cells, epithelial cells, endothelial cells, fibroblasts, smooth muscle cells and keratinocytes, and following activation, by dendritic cells (Alpdogan et al., 2005). Although it was originally described as a growth and differentiation factor for precursor B lymphocytes, subsequent studies have shown that IL-7 is critically involved in T-lymphocyte development and differentiation. Interleukin-7 signaling is essential for optimal CD8 T-cell function, homeostasis and establishment of memory (Schluns et al., 2000); it is required for the survival of most T-cell subsets, and its expression has been proposed to be important for regulating T-cell numbers.

IL-7 binds to a dimeric receptor, including IL-7Rα and γ_(c) to form a ternary complex that plays fundamental roles in extracellular matrix remodeling, development, and homeostasis of T and B cells (Mazzucchelli and Durum, 2007). IL-7 Ra also cross-reacts to form a ternary complex with thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR), and activates the TSLP pathway, resulting in T and dendritic cell proliferation in humans and further B cell development in mice (Leonard, 2002). Tight regulation of the signaling cascades activated by the complexes are therefore crucial to normal cellular function. Under-stimulation of the IL-7 pathway caused by mutations in the IL-7Rα ectodomain inhibits T and B cell development, resulting in patients with a form of severe combined immunodeficiency (SCID) (Giliani et al., 2005; Puel et al., 1998).

IL-7 has a potential role in enhancing immune reconstitution in cancer patients following cytotoxic chemotherapy. IL-7 therapy enhances immune reconstitution and can augment even limited thymic function by facilitating peripheral expansion of even small numbers of recent thymic emigrants. Therefore, IL-7 therapy could potentially repair the immune system of patients who have been depleted by cytotoxic chemotherapy (Capitini et al., 2010).

Interleukin-12 (IL-12) is a disulfide-linked heterodimer of two separately encoded subunits (p35 and p40), which are linked covalently to give rise to the so-called bioactive heterodimeric (p70) molecule (Lieschke et al., 1997; Jana et al., 2014). Apart from forming heterodimers (IL-12 and IL-23), the p40 subunit is also secreted as a monomer (p40) and a homodimer (p40₂). It is known in the art that synthesis of the heterodimer as a single chain with a linker connecting the p35 to the p40 subunit preserves the full biological activity of the heterodimer. IL-12 plays a critical role in the early inflammatory response to infection and in the generation of Th1 cells, which favor cell-mediated immunity. It has been found that overproduction of IL-12 can be dangerous to the host because it is involved in the pathogenesis of a number of autoimmune inflammatory diseases (e.g. MS, arthritis, type 1 diabetes).

The IL-12 receptor (IL-12R) is a heterodimeric complex consisting of IL-12Rβ1 and IL-12Rβ2 chains expressed on the surface of activated T-cells and natural killer cells (Trinchieri et al., 2003). The IL-12Rβ1 chain binds to the IL-12p40 subunit, whereas IL-12p35 in association with IL-12Rβ2 confers an intracellular signaling ability (Benson et al., 2011). Signal transduction through IL-12R induces phosphorylation of Janus kinase (Jak2) and tyrosine kinase (Tyk2), that phosphorylate and activate signal transducer and activator of transcription (STAT)1, STAT3, STAT4, and STAT5. The specific cellular effects of IL-12 are due mainly to activation of STAT4. IL-12 induces natural killer and T-cells to produce cytokines, in particular interferon (IFN)γ, that mediate many of the proinflammatory activities of IL-12, including CD4+ T-cell differentiation toward the Th1 phenotype (Montepaone et al., 2014).

Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity and consequent autoimmune disease. Developing drugs and methods to selectively activate regulatory T cells for the treatment of autoimmune disease is the subject of intense research and, until the development of the present invention, which can selectively deliver active interleukins at the site of inflammation, has been largely unsuccessful. Regulatory T cells (Treg) are a class of CD4+CD25+ T cells that suppress the activity of other immune cells. Treg are central to immune system homeostasis, and play a major role in maintaining tolerance to self-antigens and in modulating the immune response to foreign antigens. Multiple autoimmune and inflammatory diseases, including Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), and Graft-versus-Host Disease (GVHD) have been shown to have a deficiency of Treg cell numbers or Treg function.

Consequently, there is great interest in the development of therapies that boost the numbers and/or function of Treg cells. One treatment approach for autoimmune diseases being investigated is the transplantation of autologous, ex vivo-expanded Treg cells (Tang, Q., et al, 2013, Cold Spring Harb. Perspect. Med., 3:1-15). While this approach has shown promise in treating animal models of disease and in several early stage human clinical trials, it requires personalized treatment with the patient's own T cells, is invasive, and is technically complex. Another approach is treatment with low dose Interleukin-2 (IL-2). Treg cells characteristically express high constitutive levels of the high affinity IL-2 receptor, IL2Rαβγ, which is composed of the subunits IL2Rα (CD25), IL2Rβ (CD122), and IL2Rγ (CD132), and Treg cell growth has been shown to be dependent on IL-2 (Malek, T. R., et al., 2010, Immunity, 33:153-65).

Conversely, immune activation has also been achieved using IL-2, and recombinant IL-2 (Proleukin®) has been approved to treat certain cancers. High-dose IL-2 is used for the treatment of patients with metastatic melanoma and metastatic renal cell carcinoma with a long-term impact on overall survival.

Clinical trials of low-dose IL-2 treatment of chronic GVHD (Koreth, J., et al., 2011, N Engl J Med., 365:2055-66) and HCV-associated autoimmune vasculitis patients (Saadoun, D., et al., 2011, N Engl J Med., 365:2067-77) have demonstrated increased Treg levels and signs of clinical efficacy. New clinical trials investigating the efficacy of IL-2 in multiple other autoimmune and inflammatory diseases have been initiated. The rationale for using so-called low dose IL-2 was to exploit the high IL-2 affinity of the trimeric IL-2 receptor which is constitutively expressed on Tregs while leaving other T cells which do not express the high affinity receptor in the inactivated state. Aldesleukin (marketed as Proleukin® by Prometheus Laboratories, San Diego, Calif.), the recombinant form of IL-2 used in these trials, is associated with high toxicity. Aldesleukin, at high doses, is approved for the treatment of metastatic melanoma and metastatic renal cancer, but its side effects are so severe that its use is only recommended in a hospital setting with access to intensive care (Web address: www.proleukin.com/assets/pdf/proleukin.pdf).

The clinical trials of IL-2 in autoimmune diseases have employed lower doses of IL-2 in order to target Treg cells, because Treg cells respond to lower concentrations of IL-2 than many other immune cell types due to their expression of IL2R alpha (Klatzmann D, 2015 Nat Rev Immunol. 15:283-94). However, even these lower doses resulted in safety and tolerability issues, and the treatments used have employed daily subcutaneous injections, either chronically or in intermittent 5-day treatment courses. Therefore, there is a need for an autoimmune disease therapy that potentiates Treg cell numbers and function, that targets Treg cells more specifically than IL-2, that is safer and more tolerable, and that is administered less frequently.

One approach that has been suggested for improving the therapeutic index of IL-2-based therapy for autoimmune diseases is to use variants of IL-2 that are selective for Treg cells relative to other immune cells. IL-2 receptors are expressed on a variety of different immune cell types, including T cells, NK cells, eosinophils, and monocytes, and this broad expression pattern likely contributes to its pleiotropic effect on the immune system and high systemic toxicity. In particular, activated T effector cells express IL2Rαβγ, as do pulmonary epithelial cells. But, activating T effector cells runs directly counter to the goal of down-modulating and controlling an immune response, and activating pulmonary epithelial cells leads to known dose-limiting side effects of IL-2 including pulmonary edema. In fact, the major side effect of high-dose IL-2 immunotherapy is vascular leak syndrome (VLS), which leads to accumulation of intravascular fluid in organs such as lungs and liver with subsequent pulmonary edema and liver cell damage. There is no treatment of VLS other than withdrawal of IL-2. Low-dose IL-2 regimens have been tested in patients to avoid VLS, however, at the expense of suboptimal therapeutic results.

According to the literature, VLS is believed to be caused by the release of proinflammatory cytokines from IL-2-activated NK cells. However, there is some evidence that pulmonary edema results from direct binding of IL-2 to lung endothelial cells, which expressed low to intermediate levels of functional αβγ IL-2Rs. And, the pulmonary edema associated with interaction of IL-2 with lung endothelial cells was abrogated by blocking binding to CD25 with an anti-CD25 monoclonal antibody (mAb), in CD25-deficient host mice, or by the use of CD122-specific IL-2/anti-IL-2 mAb (IL-2/mAb) complexes, thus preventing VLS.

Treatment with interleukin cytokines other than IL-2 has been more limited. IL-15 displays immune cell stimulatory activity similar to that of IL-2 but without the same inhibitory effects, thus making it a promising immunotherapeutic candidate. Clinical trials of recombinant human IL-15 for the treatment of metastatic malignant melanoma or renal cell cancer demonstrated appreciable changes in immune cell distribution, proliferation, and activation and suggested potential antitumor activity (Conlon et. al., 2014). IL-15 is currently in clinical trials to treat various forms of cancer. However, IL-15 therapy is known to be associated with undesired and toxic effects, such as exacerbating certain leukemias, graft-versus-host disease, hypotension, thrombocytopenia, and liver injury. (Mishra A., et al., Cancer Cell, 2012, 22(5):645-55; Alpdogan O. et al., Blood, 2005, 105(2):866-73; Conlon K C et al., J Clin Oncol, 2015, 33(1):74-82.)

IL-7 promotes lymphocyte development in the thymus and maintains survival of naive and memory T cell homeostasis in the periphery. Moreover, it is important for the organogenesis of lymph nodes (LN) and for the maintenance of activated T cells recruited into the secondary lymphoid organs (SLOs) (Gao et. al., 2015). In clinical trials of IL-7, patients receiving IL-7 showed increases in both CD4+ and CD8+ T cells, with no significant increase in regulatory T cell numbers as monitored by FoxP3 expression (Sportes et al., 2008). In clinical trials reported in 2006, 2008 and 2010, patients with different kinds of cancers such as metastatic melanoma or sarcoma were injected subcutaneously with different doses of IL-7. Little toxicity was seen except for transient fevers and mild erythema. Circulating levels of both CD4+ and CD8+ T cells increased significantly and the number of Treg reduced. TCR repertoire diversity increased after IL-7 therapy. However, the anti-tumor activity of IL-7 was not well evaluated (Gao et. al., 2015). Results suggest that IL-7 therapy could enhance and broaden immune responses.

IL-12 is a pleiotropic cytokine, the actions of which create an interconnection between the innate and adaptive immunity. IL-12 was first described as a factor secreted from PMA-induced EBV-transformed B-cell lines. Based on its actions, IL-12 has been designated as cytotoxic lymphocyte maturation factor and natural killer cell stimulatory factor. Due to bridging the innate and adaptive immunity and potently stimulating the production of IFNγ, a cytokine coordinating natural mechanisms of anticancer defense, IL-12 seemed ideal candidate for tumor immunotherapy in humans. However, severe side effects associated with systemic administration of IL-12 in clinical investigations and the very narrow therapeutic index of this cytokine markedly tempered enthusiasm for the use of this cytokine in cancer patients (Lasek et. al., 2014). Approaches to IL-12 therapy in which delivery of the cytokine is tumor-targeted, which may diminish some of the previous issues with IL-12 therapy, are currently in clinical trials for cancers.

The direct use of IL-2 as an agonist to bind the IL-2R and modulate immune responses therapeutically has been problematic due its well-documented therapeutic risks, e.g., its short serum half-life and high toxicity. These risks have also limited the therapeutic development and use of other cytokines. New forms of cytokines that reduce these risks are needed. Disclosed herein are compositions and methods comprising IL-2 and IL-15 and other cytokines, functional fragments and muteins of cytokines, variants, and subunits of cytokines as well as conditionally active cytokines designed to address these risks and provide needed immunomodulatory therapeutics.

The present invention is designed to address the shortcomings of direct IL-2 therapy and therapy using other cytokines, for example using cytokine blocking moieties, e.g. steric blocking polypeptides, serum half-life extending polypeptides, targeting polypeptides, linking polypeptides, including protease cleavable linkers, and combinations thereof. Cytokines, including interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-21 IL-23), interferons (IFNs, including IFNalpha, IFNbeta and IFNgamma), tumor necrosis factors (e.g., TNFalpha, lymphotoxin), transforming growth factors (e.g., TGFbeta1, TGFbeta2, TGFbeta3), chemokines (C-X-C motif chemokine 10 (CXCL10), CCL19, CCL20, CCL21), and granulocyte macrophage-colony stimulating factor (GM-CS) are highly potent when administered to patients. As used herein, “chemokine” means a family of small cytokines with the ability to induce directed chemotaxis in nearby responsive cells Cytokines can provide powerful therapy, but are accompanied by undesired effects that are difficult to control clinically and which have limited the clinical use of cytokines. This disclosure relates to new forms of cytokines that can be used in patients with reduced or eliminated undesired effects. In particular, this disclosure relates to pharmaceutical compositions including chimeric polypeptides (fusion proteins), nucleic acids encoding fusion proteins and pharmaceutical formulations of the foregoing that contain cytokines or active fragments or muteins of cytokines that have decreased cytokine receptor activating activity in comparison to the corresponding cytokine. However, under selected conditions or in a selected biological environment the chimeric polypeptides activate their cognate receptors, often with the same or higher potency as the corresponding naturally occurring cytokine. As described herein, this is typically achieved using a cytokine blocking moiety that blocks or inhibits the receptor activating function of the cytokine, active fragment or mutein thereof under general conditions but not under selected conditions, such as those present at the desired site of cytokine activity (e.g., an inflammatory site or a tumor).

The chimeric polypeptides and nucleic acids encoding the chimeric polypeptides can be made using any suitable method. For example, nucleic acids encoding a chimeric polypeptide can be made using recombinant DNA techniques, synthetic chemistry or combinations of these techniques, and expressed in a suitable expression system, such as in CHO cells. Chimeric polypeptides can similarly be made, for example by expression of a suitable nucleic acid, using synthetic or semi-synthetic chemical techniques, and the like. In some embodiments, the blocking moiety can be attached to the cytokine polypeptide via sortase-mediated conjugation. “Sortases” are transpeptidases that modify proteins by recognizing and cleaving a carboxyl-terminal sorting signal embedded in or terminally attached to a target protein or peptide. Sortase A catalyzes the cleavage of the LPXTG motif (SEQ ID No.: 442) (where X is any standard amino acid) between the Thr and Gly residue on the target protein, with transient attachment of the Thr residue to the active site Cys residue on the enzyme, forming an enzyme-thioacyl intermediate. To complete transpeptidation and create the peptide-monomer conjugate, a biomolecule with an N-terminal nucleophilic group, typically an oligoglycine motif, attacks the intermediate, displacing Sortase A and joining the two molecules.

To form the cytokine-blocking moiety fusion protein, the cytokine polypeptide is first tagged at the N-terminus with a polyglycine sequence, or alternatively, with at the C-terminus with a LPXTG motif (SEQ ID NO.: 442). The blocking moiety or other element has respective peptides attached that serve as acceptor sites for the tagged polypeptides. For conjugation to domains carrying a LPXTG (SEQ ID NO.: 442) acceptor peptide attached via its N-terminus, the polypeptide will be tagged with an N-terminal poly-glycine stretch. For conjugation to domain carrying a poly-glycine peptide attached via its C-terminus, the polypeptide will be tagged at its C-terminus with a LPXTG (SEQ ID NO.: 442) sortase recognition sequence. Recognizing poly-glycine and LPXTG (SEQ ID NO.: 442) sequences, sortase will form a peptide bond between polymer-peptide and tagged polypeptides. The sortase reaction cleaves off glycine residues as intermediates and occurs at room temperature.

A variety of mechanisms can be exploited to remove or reduce the inhibition caused by the blocking moiety. For example, the pharmaceutical compositions can include a cytokine moiety and a blocking moiety, e.g. a steric blocking moiety, with a protease cleavable linker comprising a protease cleavage site located between the cytokine and cytokine blocking moiety or within the cytokine blocking moiety. When the protease cleavage site is cleaved, the blocking moiety can dissociate from cytokine, and the cytokine can then activate cytokine receptor. A cytokine moiety can also be blocked by a specific blocking moiety, such as an antibody, which binds an epitope found on the relevant cytokine.

Any suitable linker can be used. For example, the linker can comprise glycine-glycine, a sortase-recognition motif, or a sortase-recognition motif and a peptide sequence (Gly₄Ser)_(n)(SEQ ID NO.: 443) or (Gly₃Ser)_(n), (SEQ ID NO.: 444) wherein n is 1, 2, 3, 4 or 5. Typically, the sortase-recognition motif comprises a peptide sequence LPXTG (SEQ ID NO.: 442), where X is any amino acid. In some embodiments, the covalent linkage is between a reactive lysine residue attached to the C-terminal of the cytokine polypeptide and a reactive aspartic acid attached to the N-terminal of the blocker or other domain. In other embodiments, the covalent linkage is between a reactive aspartic acid residue attached to the N-terminal of the cytokine polypeptide and a reactive lysine residue attached to the C-terminal of said blocker or other domain.

Accordingly, as described in detail herein, the cytokine blocking moieties used can be steric blockers. As used herein, a “steric blocker” refers to a polypeptide or polypeptide moiety that can be covalently bonded to a cytokine polypeptide directly or indirectly through other moieties such as linkers, for example in the form of a chimeric polypeptide (fusion protein), but otherwise does not covalently bond to the cytokine polypeptide. A steric blocker can non-covalently bond to the cytokine polypeptide, for example though electrostatic, hydrophobic, ionic or hydrogen bonding. A steric blocker typically inhibits or blocks the activity of the cytokine moiety due to its proximity to the cytokine moiety and comparative size. The steric inhibition of the cytokine moiety can be removed by spatially separating the cytokine moiety from the steric blocker, such as by enzymatically cleaving a fusion protein that contains a steric blocker and a cytokine polypeptide at a site between the steric blocker and the cytokine polypeptide.

As described in greater detail herein, the blocking function can be combined with or due to the presence of additional functional components in the pharmaceutical composition, such as a targeting domain, a serum half-life extension element, and protease-cleavable linking polypeptides. For example, a serum half-life extending polypeptide can also be a steric blocker.

In the interest of presenting a concise disclosure of the full scope of the invention, aspects of the invention are described in detail using the cytokine IL-2 as an exemplary cytokine. However, the invention and this disclosure are not limited to IL-2. It will be clear to a person of skill in the art that this disclosure, including the disclosed methods, polypeptides and nucleic acids, adequately describes and enables the use of other cytokines, fragments, variants, cytokine subunits, and muteins, such as IL-2, IL-7, IL-12, IL-15, IL-18, IL-21 IL-23, IFNalpha, IFNbeta, IFNgamma, TNFalpha, lymphotoxin, TGF-beta1, TGFbeta2, TGFbeta3, GM-CSF, CXCL10, CCL19, CCL20, CCL21 and functional fragments or muteins of any of the foregoing. Preferred cytokines for use in the fusion proteins disclosed herein are IL-2, IL-12, IFNalpha, IFNbeta, IFNgamma, muteins, functional variants, and functional fragments, or subunits of any of the foregoing. For example, the cytokine a IL-12 cytokine may be a p35 subunit, a p40 subunit, a heterodimer.

Various elements ensure the delivery and activity of IL-2 preferentially at the site of desired IL-2 activity and to severely limit systemic exposure to the interleukin via a blocking and/or a targeting strategy preferentially linked to a serum half-life extension strategy. In this serum half-life extension strategy, the blocked version of interleukin circulates for extended times (preferentially 1-2 or more weeks) but the activated version has the typical serum half-life of the interleukin.

By comparison to a serum half-life extended version, the serum half-life of IL-2 administered intravenously is only ˜10 minutes due to distribution into the total body extracellular space, which is large, ˜15 L in an average sized adult. Subsequently, IL-2 is metabolized by the kidneys with a half-life of ˜2.5 hours. (Smith, K. “Interleukin 2 immunotherapy.” Therapeutic Immunology 240 (2001)). By other measurements, IL-2 has a very short plasma half-life of 85 minutes for intravenous administration and 3.3 hours subcutaneous administration (Kirchner, G. I., et al., 1998, Br J Clin Pharmacol. 46:5-10). In some embodiments of this invention, the half-life extension element is linked to the interleukin via a linker which is cleaved at the site of action (e.g. by inflammation-specific or tumor-specific proteases) releasing the interleukin's full activity at the desired site and also separating it from the half-life extension of the uncleaved version. In such embodiments, the fully active and free interleukin would have very different pharmacokinetic (pK) properties—a half-life of hours instead of weeks. In addition, exposure to active cytokine is limited to the site of desired cytokine activity (e.g., an inflammatory site or tumor) and systemic exposure to active cytokine, and associated toxicity and side effects, are reduced.

Other cytokines envisioned in this invention have similar pharmacology (e.g. IL-15 as reported by Blood 2011 117:4787-4795; doi: doi.org/10.I182/blood-2010-10-311456) as IL-2 and accordingly, the designs of this invention address the shortcomings of using these agents directly, and provide chimeric polypeptides that can have extended half-life and/or be targeted to a site of desired activity (e.g., a site of inflammation or a tumor).

If desired, IL-2 can be engineered to bind the IL-2R complex generally or one of the three IL-2R subunits specifically with an affinity that differs from that of the corresponding wild-type IL-2, for example toto selectively activate Tregs or Teff. For example, IL-2 polypeptides that are said to have higher affinity for the trimeric form of the IL-2 receptor relative to the dimeric beta/gamma form of the I1-2 receptor in comparison to wild type IL-2 can have an amino acid sequence that includes one of the following sets of mutations with respect to SEQ ID NO:1 (a mature IL-2 protein comprising amino acids 21-153 of human IL-2 having the Uniprot Accession No. P60568-1): (a) K64R, V69A, and Q74P; (b) V69A, Q74P, and T101A; (c) V69A, Q74P, and 1128T; (d) N30D, V69A, Q74P, and F103S; (e) K49E, V69A, A73V, and K76E; (f) V69A, Q74P, T101A, and T133N; (g) N30S, V69A, Q74P, and I128A; (h) V69A, Q74P, N88D, and S99P; (i) N30S, V69A, Q74P, and I128T; (j) K9T, Q11R, K35R, V69A, and Q74P; (k) A1T, M46L, K49R, E61D, V69A, and H79R; (1) K48E, E68D, N71T, N90H, F103S, and 1114V; (m) S4P, T10A, Q11R, V69A, Q74P, N88D, and T133A; (n) E15K, N30S Y31H, K35R, K48E, V69A, Q74P, and I92T; (o) N30S, E68D, V69A, N71A, Q74P, S75P, K76R, and N90H; (p) N30S, Y31C, T37A, V69A, A73V, Q74P, H79R, and I128T; (q) N26D, N29S, N30S, K54R, E67G, V69A, Q74P, and I92T; (r) K8R, Q13R, N26D, N30T, K35R, T37R, V69A, Q74P, and I92T; and (s) N29S, Y31H, K35R, T37A, K48E, V69A, N71R, Q74P, N88D, and 189V. This approach can also be applied to prepare muteins of other cytokines including interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-23), interferons (IFNs, including IFNalpha, IFNbeta and IFNgamma), tumor necrosis factors (e.g., TNFalpha, lymphotoxin), transforming growth factors (e.g., TGFbeta1, TGFbeta2, TGFbeta3) and granulocyte macrophage-colony stimulating factor (GM-CS). For example, muteins can be prepared that have desired binding affinity for a cognate receptor.

As noted above, any of the mutant IL-2 polypeptides disclosed herein can include the sequences described; they can also be limited to the sequences described and otherwise identical to SEQ ID NO:1. Moreover, any of the mutant IL-2 polypeptides disclosed herein can optionally include a substitution of the cysteine residue at position 125 with another residue (e.g., serine) and/or can optionally include a deletion of the alanine residue at position 1 of SEQ ID NO:1.

Another approach to improving the therapeutic index of an IL-2 based therapy is to optimize the pharmacokinetics of the molecule to maximally activate Treg cells. Early studies of IL-2 action demonstrated that IL-2 stimulation of human T cell proliferation in vitro required a minimum of 5-6 hours exposure to effective concentrations of IL-2 (Cantrell, D. A., et. al., 1984, Science, 224: 1312-1316). When administered to human patients, IL-2 has a very short plasma half-life of 85 minutes for intravenous administration and 3.3 hours subcutaneous administration (Kirchner, G. I., et al., 1998, Br J Clin Pharmacol. 46:5-10). Because of its short half-life, maintaining circulating IL-2 at or above the level necessary to stimulate T cell proliferation for the necessary duration necessitates high doses that result in peak IL-2 levels significantly above the EC50 for Treg cells or will require frequent administration. These high IL-2 peak levels can activate IL2Rβγ receptors and have other unintended or adverse effects, for example VLS as noted above. An IL-2 analog, or a multifunctional protein with IL-2 attached to a domain that enables binding to the FcRn receptor, with a longer circulating half-life than IL-2 can achieve a target drug concentration for a specified period of time at a lower dose than IL-2, and with lower peak levels. Such an IL-2 analog will therefore require either lower doses or less frequent administration than IL-2 to effectively stimulate Treg cells. Less frequent subcutaneous administration of an IL-2 drug will also be more tolerable for patients. A therapeutic with these characteristics will translate clinically into improved pharmacological efficacy, reduced toxicity, and improved patient compliance with therapy. Alternatively, IL-2 or muteins of IL-2 (herein, “IL-2*”) can be selectively targeted to the intended site of action (e.g. sites of inflammation or a tumor). This targeting can be achieved by one of several strategies, including the addition of domains to the administered agent that comprise blockers of the IL-2 (or muteins) that are cleaved away or by targeting domains or a combination of the two.

In some embodiments, IL-2* partial agonists can be tailored to bind with higher or lower affinity depending on the desired target; for example, an IL-2* can be engineered to bind with enhanced affinity to one of the receptor subunits and not the others. These types of partial agonists, unlike full agonists or complete antagonists, offer the ability to tune the signaling properties to an amplitude that elicits desired functional properties while not meeting thresholds for undesired properties. Given the differential activities of the partial agonists, a repertoire of IL-2 variants could be engineered to exhibit an even finer degree of distinctive signaling activities, ranging from almost full to partial agonism to complete antagonism.

In some embodiments, the IL-2* has altered affinity for IL-2Rα. In some embodiments, the IL-2* has a higher affinity for IL-2Rα than wild-type IL-2. In other embodiments, the IL-2* has altered affinity for IL-2Rβ. In one embodiment, IL-2* has enhanced binding affinity for IL-2Rβ, e.g., the N-terminus of IL-2Rβ, that eliminates the functional requirement for IL-2Rα. In another embodiment, an IL-2* is generated that has increased binding affinity for IL-2Rβ but that exhibited decreased binding to IL-2Rγ, and thereby is defective IL-2Rβγ heterodimerization and signaling.

Blocking moieties, described in further detail below, can also be used to favor binding to or activation of one or more receptors. In one embodiment, blocking moieties are added such that IL-2Rβγ binding or activation is blocked but IL-2Rα binding or activation is not changed. In another embodiment, blocking moieties are added such that IL-2Rα binding or activation is diminished. In another embodiment, blocking moieties are added such that binding to and or activation of all three receptors is inhibited. This blocking may be relievable by removal of the blocking moieties in a particular environment, for example by proteolytic cleavage of a linker linking one or more blocking moieties to the cytokine.

A similar approach can be applied to improve other cytokines, particularly for use as immunostimulatory agents, for example for treating cancer. For example, in this aspect, the pharmacokinetics and/or pharmacodynamics of the cytokine (e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-21 IL-23, IFNalpha, IFNbeta and IFNgamma, TNFalpha, lymphotoxin, TGFbeta1, TGFbeta2, TGFbeta3 GM-CSF, CXCL10, CCL19, CCL20, and CCL21 can be tailored to maximally activate effector cells (e.g., effect T cells, NK cells) and/or cytotoxic immune response promoting cells (e.g., induce dendritic cell maturation) at a site of desired activity, such as in a tumor, but preferably not systemically.

Thus, provided herein are pharmaceutical compositions comprising at least one cytokine polypeptide, such as interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23), interferons (IFNs, including IFNalpha, IFNbeta and IFNgamma), tumor necrosis factors (e.g., TNFalpha, lymphotoxin), transforming growth factors (e.g., TGFbeta1, TGFbeta2, TGFbeta3), chemokines (e.g. CXCL10, CCL19, CCL20, CCL21) and granulocyte macrophage-colony stimulating factor (GM-CS) or a functional fragment or mutein of any of the foregoing. The polypeptide typically also includes at least one linker amino acid sequence, wherein the amino acid sequence is in certain embodiments capable of being cleaved by an endogenous protease. In one embodiment, the linker comprises an amino acid sequence comprising HSSKLQ (SEQ ID NO.: 25), GPLGVRG (SEQ ID NO.: 445), IPVSLRSG (SEQ ID NO.: 446), VPLSLYSG (SEQ ID NO. 447), or SGESPAYYTA (SEQ ID NO. 448). In other embodiments, the chimeric polypeptide further contains a blocking moiety, e.g. a steric blocking polypeptide moiety, capable of blocking the activity of the interleukin polypeptide. The blocking moiety, for example, can comprise a human serum albumin (HSA) binding domain or an optionally branched or multi-armed polyethylene glycol (PEG). Alternatively, the pharmaceutical composition comprises a first cytokine polypeptide or a fragment thereof, and blocking moiety, e.g. a steric blocking polypeptide moiety, wherein the blocking moiety blocks the activity of the cytokine polypeptide on the cytokine receptor, and wherein the blocking moiety in certain embodiments comprises a protease cleavable domain. In some embodiments, blockade and reduction of cytokine activity is achieved simply by attaching additional domains with very short linkers to the N or C terminus of the interleukin domain. In such embodiments, it is anticipated the blockade is relieved by protease digestion of the blocking moiety or of the short linker that tethers the blocker to the interleukin. Once the domain is clipped or is released, it will no longer be able to achieve blockade of cytokine activity.

The pharmaceutical composition e.g., chimeric polypeptide can comprise two or more cytokines, which can be the same cytokine polypeptide or different cytokine polypeptides. For example, the two or more different types of cytokines have complementary functions. In some examples, a first cytokine is IL-2 and a second cytokine is IL-12. In some embodiments, each of the two or more different types of cytokine polypeptides have activities that modulate the activity of the other cytokine polypeptides. In some examples of chimeric polypeptides that contain two cytokine polypeptides, a first cytokine polypeptide is T-cell activating, and a second cytokine polypeptide is non-T-cell-activating. In some examples of chimeric polypeptides that contain two cytokine polypeptides, a first cytokine is a chemoattractant, e.g. CXCL10, and a second cytokine is an immune cell activator.

Preferably, the cytokine polypeptides (including functional fragments) that are included in the fusion proteins disclosed herein are not mutated or engineered to alter the properties of the naturally occurring cytokine, including receptor binding affinity and specificity or serum half-life. However, changes in amino acid sequence from naturally occurring (including wild type) cytokine are acceptable to facilitate cloning and to achieve desired expression levels, for example.

Blocking Moiety

The blocking moiety can be any moiety that inhibits the ability of the cytokine to bind and/or activate its receptor. The blocking moiety can inhibit the ability of the cytokine to bind and/or activate its receptor sterically blocking and/or by noncovalently binding to the cytokine. Examples of suitable blocking moieties include the full length or a cytokine-binding fragment or mutein of the cognate receptor of the cytokine. Antibodies and fragments thereof including, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody a single chain variable fragment (scFv), single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain of camelid-type nanobody (VHH), a dAb and the like that bind the cytokine can also be used. Other suitable antigen-binding domain that bind the cytokine can also be used, include non-immunoglobulin proteins that mimic antibody binding and/or structure such as, anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, DARPins, fynomers, kunitz domain peptides, monobodies, and binding domains based on other engineered scaffolds such as SpA, GroEL, fibronectin, lipocallin and CTLA4 scaffolds. Further examples of suitable blocking polypeptides include polypeptides that sterically inhibit or block binding of the cytokine to its cognate receptor. Advantageously, such moieties can also function as half-life extending elements. For example, a peptide that is modified by conjugation to a water-soluble polymer, such as PEG, can sterically inhibit or prevent binding of the cytokine to its receptor. Polypeptides, or fragments thereof, that have long serum half-lives can also be used, such as serum albumin (human serum albumin), immunoglobulin Fc, transferrin and the like, as well as fragments and muteins of such polypeptides. Antibodies and antigen-binding domains that bind to, for example, a protein with a long serum half-life such as HSA, immunoglobulin or transferrin, or to a receptor that is recycled to the plasma membrane, such as FcRn or transferrin receptor, can also inhibit the cytokine, particularly when bound to their antigen. Examples of such antigen-binding polypeptides include a single chain variable fragment (scFv), single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain of camelid-type nanobody (VHH), a dAb and the like. Other suitable antigen-binding domain that bind the cytokine can also be used, include non-immunoglobulin proteins that mimic antibody binding and/or structure such as, anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, DARPins, fynomers, kunitz domain peptides, monobodies, and binding domains based on other engineered scaffolds such as SpA, GroEL, fibronectin, lipocallin and CTLA4 scaffolds.

In illustrative examples, when IL-2 is the cytokine in the chimeric polypeptide, the blocking moiety can be the full length or fragment or mutein of the alpha chain of IL-2 receptor (IL-2Rα) or beta (IL-2Rβ) or gamma chain of IL-2 receptor (IL-2Rγ), an anti-IL-2 single-domain antibody (dAb) or scFv, a Fab, an anti-CD25 antibody or fragment thereof, and anti-HSA dAb or scFv, and the like. As described further herein, when an antibody fragement is used to attenuate the activity of the cytokine polypeptide, the blocking moiety in the fusion protein can be a single chain antibody binding fragment, such as an scFv. The blocking moiety can also be half of a two chain antigen binding fragment such as a VH-CH1, which associates with a complementary VL-CL on a second polypeptide for form an antibody binding site the binds the cytokine polypeptide.

In vivo Half-life Extension Elements

Preferably, the chimeric polypeptides comprise an in vivo half-life extension element. Increasing the in vivo half-life of therapeutic molecules with naturally short half-lives allows for a more acceptable and manageable dosing regimen without sacrificing effectiveness. As used herein, a “half-life extension element” is a part of the chimeric polypeptide that increases the in vivo half-life and improve pK, for example, by altering its size (e.g., to be above the kidney filtration cutoff), shape, hydrodynamic radius, charge, or parameters of absorption, biodistribution, metabolism, and elimination. An exemplary way to improve the pK of a polypeptide is by expression of an element in the polypeptide chain that binds to receptors that are recycled to the plasma membrane of cells rather than degraded in the lysosomes, such as the FcRn receptor on endothelial cells and transferrin receptor. Three types of proteins, e.g., human IgGs, HSA (or fragments), and transferrin, persist for much longer in human serum than would be predicted just by their size, which is a function of their ability to bind to receptors that are recycled rather than degraded in the lysosome. These proteins, or fragments of them that retain the FcRn binding are routinely linked to other polypeptides to extend their serum half-life. In one embodiment, the half-life extension element is a human serum albumin (HSA) binding domain. HSA (SEQ ID NO: 2) may also be directly bound to the pharmaceutical compositions or bound via a short linker. Fragments of HSA may also be used. HSA and fragments thereof can function as both a blocking moiety and a half-life extension element. Human IgGs and Fc fragments can also carry out a similar function.

The serum half-life extension element can also be antigen-binding polypeptide that binds to a protein with a long serum half-life such as serum albumin, transferrin and the like. Examples of such polypeptides include antibodies and fragments thereof including, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody a single chain variable fragment (scFv), single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain of camelid-type nanobody (VHH), a dAb and the like. Other suitable antigen-binding domain include non-immunoglobulin proteins that mimic antibody binding and/or structure such as, anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, DARPins, fynomers, kunitz domain peptides, monobodies, and binding domains based on other engineered scaffolds such as SpA, GroEL, fibronectin, lipocallin and CTLA4 scaffolds. Further examples of antigen-binding polypeptides include a ligand for a desired receptor, a ligand-binding portion of a receptor, a lectin, and peptides that binds to or associates with one or more target antigens.

Some preferred serum half-life extension elements are polypeptides that comprise complementarity determining regions (CDRs), and optionally non-CDR loops. Advantageously, such serum half-life extension elements can extend the serum half-life of the cytokine, and also function as inhibitors of the cytokine (e.g., via steric blocking, non-covalent interaction or combination thereof) and/or as targeting domains. In some instances, the serum half-life extension elements are domains derived from an immunoglobulin molecule (Ig molecule) or engineered protein scaffolds that mimic antibody structure and/or binding activity. The Ig may be of any class or subclass (IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM etc). A polypeptide chain of an Ig molecule folds into a series of parallel beta strands linked by loops. In the variable region, three of the loops constitute the “complementarity determining regions” (CDRs) which determine the antigen binding specificity of the molecule. An IgG molecule comprises at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding fragment thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs) with are hypervariable in sequence and/or involved in antigen recognition and/or usually form structurally defined loops, interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments of this disclosure, at least some or all of the amino acid sequences of FR1, FR2, FR3, and FR4 are part of the “non-CDR loop” of the binding moieties described herein. A variable domain of an immunoglobulin molecule has several beta strands that are arranged in two sheets. The variable domains of both light and heavy immunoglobulin chains contain three hypervariable loops, or complementarity-determining regions (CDRs). The three CDRs of a V domain (CDR1, CDR2, CDR3) cluster at one end of the beta barrel. The CDRs are the loops that connect beta strands B-C, C′-C″, and F-G of the immunoglobulin fold, whereas the bottom loops that connect beta strands AB, CC′, C″-D and E-F of the immunoglobulin fold, and the top loop that connects the D-E strands of the immunoglobulin fold are the non-CDR loops. In some embodiments of this disclosure, at least some amino acid residues of a constant domain, CH1, CH2, or CH3, are part of the “non-CDR loop” of the binding moieties described herein. Non-CDR loops comprise, in some embodiments, one or more of AB, CD, EF, and DE loops of a C1-set domain of an Ig or an Ig-like molecule; AB, CC′, EF, FG, BC, and EC′ loops of a C2-set domain of an Ig or an Ig-like molecule; DE, BD, GF, A(A1A2)B, and EF loops of I(Intermediate)-set domain of an Ig or Ig-like molecule.

Within the variable domain, the CDRs are believed to be responsible for antigen recognition and binding, while the FR residues are considered a scaffold for the CDRs. However, in certain cases, some of the FR residues play an important role in antigen recognition and binding. Framework region residues that affect Ag binding are divided into two categories. The first are FR residues that contact the antigen, thus are part of the binding-site, and some of these residues are close in sequence to the CDRs. Other residues are those that are far from the CDRs in sequence, but are in close proximity to it in the 3-D structure of the molecule, e.g., a loop in heavy chain.

The binding moieties are any kinds of polypeptides. For example, in certain instances the binding moieties are natural peptides, synthetic peptides, or fibronectin scaffolds, or engineered bulk serum proteins. The bulk serum protein comprises, for example, albumin, fibrinogen, or a globulin. In some embodiments, the binding moieties are engineered scaffolds. Engineered scaffolds comprise, for example, sdAb, a scFv, a Fab, a VHH, a fibronectin type III domain, immunoglobulin-like scaffold (as suggested in Halaby et al., 1999. Prot Eng 12(7):563-571), DARPin, cystine knot peptide, lipocalin, three-helix bundle scaffold, protein G-related albumin-binding module, or a DNA or RNA aptamer scaffold.

In some cases, the serum half-life extending element comprises a binding site for a bulk serum protein. In some embodiments, the CDRs provide the binding site for the bulk serum protein. The bulk serum protein is, in some examples, a globulin, albumin, transferrin, IgG1, IgG2, IgG4, IgG3, IgA monomer, Factor XIII, Fibrinogen, IgE, or pentameric IgM. In some embodiments, the CDR form a binding site for an immunoglobulin light chain, such as an Igκ free light chain or an Igλ free light chain.

The serum half-life extension element can be any type of binding domain, including but not limited to, domains from a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody. In some embodiments, the binding moiety is a single chain variable fragment (scFv), single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain (VHH) of camelid derived nanobody. In other embodiments, the binding moieties are non-Ig binding domains, i.e., antibody mimetic, such as anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, DARPins, fynomers, kunitz domain peptides, and monobodies.

In other embodiments, the serum half-life extension element can be a water-soluble polymer or a peptide that is conjugated to a water-soluble polymer, such as PEG. “PEG,” “polyethylene glycol” and “poly(ethylene glycol)” as used herein, are interchangeable and encompass any nonpeptidic water-soluble poly(ethylene oxide). The term “PEG” also means a polymer that contains a majority, that is to say, greater than 50%, of —OCH₂CH₂— repeating subunits. With respect to specific forms, the PEG can take any number of a variety of molecular weights, as well as structures or geometries such as “branched,” “linear,” “forked,” “multifunctional,” and the like, to be described in greater detail below. The PEG is not limited to a particular structure and can be linear (e.g., an end capped, e.g., alkoxy PEG or a bifunctional PEG), branched or multi-armed (e.g., forked PEG or PEG attached to a polyol core), a dendritic (or star) architecture, each with or without one or more degradable linkages. Moreover, the internal structure of the PEG can be organized in any number of different repeat patterns and can be selected from the group consisting of homopolymer, alternating copolymer, random copolymer, block copolymer, alternating tripolymer, random tripolymer, and block tripolymer. PEGs can be conjugated to polypeptide and peptides through any suitable method. Typically, a reactive PEG derivative, such as N-hydroxysuccinamidyl ester PEG, is reacted with a peptide or polypeptide that includes amino acids with a side chain that contains an amine, sulfhydryl, carboxylic acid or hydroxyl functional group, such as cysteine, lysine, asparagine, glutamine, theonine, tyrosine, serine, aspartic acid, and glutamic acid.

Targeting and Retention Domains

For certain applications, it may be desirable to maximize the amount of time the construct is present in its desired location in the body. This can be achieved by including one further domain in the chimeric polypeptide (fusion protein) to influence its movements within the body. For example, the chimeric nucleic acids can encode a domain that directs the polypeptide to a location in the body, e.g., tumor cells or a site of inflammation; this domain is termed a “targeting domain” and/or encode a domain that retains the polypeptide in a location in the body, e.g., tumor cells or a site of inflammation; this domain is termed a “retention domain”. In some embodiments a domain can function as both a targeting and a retention domain. In some embodiments, the targeting domain and/or retention domain are specific to a protease-rich environment. In some embodiments, the encoded targeting domain and/or retention domain are specific for regulatory T cells (Tregs), for example targeting the CCR4 or CD39 receptors. Other suitable targeting and/or retention domains comprise those that have a cognate ligand that is overexpressed in inflamed tissues, e.g., the IL-1 receptor, or the IL-6 receptor. In other embodiments, the suitable targeting and/or retention domains comprise those who have a cognate ligand that is overexpressed in tumor tissue, e.g., Epcam, CEA or mesothelin. In some embodiments, the targeting domain is linked to the interleukin via a linker which is cleaved at the site of action (e.g. by inflammation or cancer specific proteases) releasing the interleukin full activity at the desired site. In some embodiments, the targeting and/or retention domain is linked to the interleukin via a linker which is not cleaved at the site of action (e.g. by inflammation or cancer specific proteases), causing the cytokine to remain at the desired site.

Antigens of choice, in some cases, are expressed on the surface of a diseased cell or tissue, for example a tumor or a cancer cell. Antigens useful for tumor targeting and retention include but are not limited to EpCAM, EGFR, HER-2, HER-3, c-Met, FOLR1, and CEA. Pharmaceutical compositions disclosed herein, also include proteins comprising two targeting and/or retention domains that bind to two different target antigens known to be expressed on a diseased cell or tissue. Exemplary pairs of antigen binding domains include but are not limited to EGFR/CEA, EpCAM/CEA, and HER-2/HER-3.

Suitable targeting and/or retention domains include antigen-binding domains, such as antibodies and fragments thereof including, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody a single chain variable fragment (scFv), single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain of camelid-type nanobody (VHH), a dAb and the like. Other suitable antigen-binding domain include non-immunoglobulin proteins that mimic antibody binding and/or structure such as, anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, DARPins, fynomers, kunitz domain peptides, monobodies, and binding domains based on other engineered scaffolds such as SpA, GroEL, fibronectin, lipocallin and CTLA4 scaffolds. Further examples of antigen-binding polypeptides include a ligand for a desired receptor, a ligand-binding portion of a receptor, a lectin, and peptides that binds to or associates with one or more target antigens.

In some embodiments, the targeting and/or retention domains specifically bind to a cell surface molecule. In some embodiments, the targeting and/or retention domains specifically bind to a tumor antigen. In some embodiments, the targeting polypeptides specifically and independently bind to a tumor antigen selected from at least one of Fibroblast activation protein alpha (FAPa), Trophoblast glycoprotein (5T4), Tumor-associated calcium signal transducer 2 (Trop2), Fibronectin EDB (EDB-FN), fibronectin EIIIB domain, CGS-2, EpCAM, EGFR, HER-2, HER-3, cMet, CEA, and FOLR1. In some embodiments, the targeting polypeptides specifically and independently bind to two different antigens, wherein at least one of the antigens is a tumor antigen selected from EpCAM, EGFR, HER-2, HER-3, cMet, CEA, and FOLR1.

The targeting and/or retention antigen can be a tumor antigen expressed on a tumor cell. Tumor antigens are well known in the art and include, for example, EpCAM, EGFR, HER-2, HER-3, c-Met, FOLR1, PSMA, CD38, BCMA, and CEA. 5T4, AFP, B7-H3, Cadherin-6, CAIX, CD117, CD123, CD138, CD166, CD19, CD20, CD205, CD22, CD30, CD33, CD352, CD37, CD44, CD52, CD56, CD70, CD71, CD74, CD79b, DLL3, EphA2, FAP, FGFR2, FGFR3, GPC3, gpA33, FLT-3, gpNMB, HPV-16 E6, HPV-16 E7, ITGA2, ITGA3, SLC39A6, MAGE, mesothelin, Muc1, Muc16, NaPi2b, Nectin-4, P-cadherin, NY-ESO-1, PRLR, PSCA, PTK7, ROR1, SLC44A4, SLTRK5, SLTRK6, STEAP1, TIM1, Trop2, WT1.

The targeting and/or retention antigen can be an immune checkpoint protein. Examples of immune checkpoint proteins include but are not limited to CD27, CD137, 2B4, TIGIT, CD155, ICOS, HVEM, CD40L, LIGHT, TIM-1, OX40, DNAM-1, PD-L1, PD1, PD-L2, CTLA-4, CD8, CD40, CEACAM1, CD48, CD70, A2AR, CD39, CD73, B7-H3, B7-H4, BTLA, IDO1, IDO2, TDO, KIR, LAG-3, TIM-3, or VISTA.

The targeting and/or retention antigen can be a cell surface molecule such as a protein, lipid or polysaccharide. In some embodiments, a targeting and/or retention antigen is a on a tumor cell, virally infected cell, bacterially infected cell, damaged red blood cell, arterial plaque cell, inflamed or fibrotic tissue cell. The targeting and/or retention antigen can comprise an immune response modulator. Examples of immune response modulator include but are not limited to granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), interleukin 2 (IL-2), interleukin 3 (IL-3), interleukin 12 (IL-12), interleukin 15 (IL-15), B7-1 (CD80), B7-2 (CD86), GITRL, CD3, or GITR.

The targeting and/or retention antigen can be a cytokine receptor. Examples, of cytokine receptors include but are not limited to Type I cytokine receptors, such as GM-CSF receptor, G-CSF receptor, Type I IL receptors, Epo receptor, LIF receptor, CNTF receptor, TPO receptor, Type II Cytokine receptors, such as IFN-alpha receptor (IFNAR1, IFNAR2), IFB-beta receptor, IFN-gamma receptor (IFNGR1, IFNGR2), Type II IL receptors; chemokine receptors, such as CC chemokine receptors, CXC chemokine receptors, CX3C chemokine receptors, XC chemokine receptors; tumor necrosis receptor superfamily receptors, such as TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF7/CD27, TNFRSF1A/TNFR1/CD120a, TNFRSF1B/TNFR2/CD120b; TGF-beta receptors, such as TGF-beta receptor 1, TGF-beta receptor 2; Ig super family receptors, such as IL-1 receptors, CSF-1R, PDGFR (PDGFRA, PDGFRB), SCFR.

Linkers

As stated above, the pharmaceutical compositions comprise one or more linker sequences. A linker sequence serves to provide flexibility between polypeptides, such that, for example, the blocking moiety is capable of inhibiting the activity of the cytokine polypeptide. The linker sequence can be located between any or all of the cytokine polypeptide, the serum half-life extension element, and/or the blocking moiety. As described herein at least one of the linkers is protease cleavable, and contains a (one or more) cleavage site for a (one or more) desired protease. Preferably, the desired protease is enriched or selectively expressed at the desired site of cytokine activity (e.g., the tumor microenvironment). Thus, the fusion protein is preferentially or selectively cleaved at the site of desired cytokine activity.

Suitable linkers can be of different lengths, such as from 1 amino acid (e.g., Gly) to 20 amino acids, from 2 amino acids to 15 amino acids, from 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 amino acids.

The orientation of the components of the pharmaceutical composition, are largely a matter of design choice and it is recognized that multiple orientations are possible and all are intended to be encompassed by this disclosure. For example, a blocking moiety can be located C-terminally or N-terminally to a cytokine polypeptide.

Proteases known to be associated with diseased cells or tissues include but are not limited to serine proteases, cysteine proteases, aspartate proteases, threonine proteases, glutamic acid proteases, metalloproteases, asparagine peptide lyases, serum proteases, cathepsins, Cathepsin B, Cathepsin C, Cathepsin D, Cathepsin E, Cathepsin K, Cathepsin L, kallikreins, hK1, hK10, hK15, plasmin, collagenase, Type IV collagenase, stromelysin, Factor Xa, chymotrypsin-like protease, trypsin-like protease, elastase-like protease, subtilisin-like protease, actinidain, bromelain, calpain, caspases, caspase-3, Mir-CP, papain, HIV-protease, HSV protease, CMV protease, chymosin, renin, pepsin, matriptase, legumain, plasmepsin, nepenthesin, metalloexopeptidases, metallendopeptidases, matrix metalloproteases (MMP), MMP1, MMP2, MMP3, MMP8, MMP9, MMP13, MMP11, MMP14, urokinase plasminogen activator (uPA), enterokinase, prostate-specific antigen (PSA, hK3), interleukin-10β converting enzyme, thrombin, FAP (FAP-a), dipeptidyl peptidase, meprins, granzymes and dipeptidyl peptidase IV (DPPIV/CD26). Proteases capable of cleaving amino acid sequences encoded by the chimeric nucleic acid sequences provided herein can, for example, be selected from the group consisting of a prostate specific antigen (PSA), a matrix metalloproteinase (MMP), an A Disintigrin and a Metalloproteinase (ADAM), a plasminogen activator, a cathepsin, a caspase, a tumor cell surface protease, and an elastase. The MMP can, for example, be matrix metalloproteinase 2 (MMP2) or matrix metalloproteinase 9 (MMP9).

Proteases useful in the methods disclosed herein are presented in Table 1, and exemplary proteases and their cleavage site are presented in Table 1a:

TABLE 1 Proteases relevant to inflammation and cancer Protease Specificity Other aspects Secreted by killer T cells: Granzyme B (grB) Cleaves after Asp Type of serine protease; strongly residues (asp-ase) implicated in inducing perforin-dependent target cell apoptosis Granzyme A (grA) trypsin-like, cleaves after Type of serine protease; basic residues Granzyme H (grH) Unknown substrate Type of serine protease; specificity Other granzymes are also secreted by killer T cells, but not all are present in humans Caspase-8 Cleaves after Asp Type of cysteine protease; plays essential residues role in TCR-induced cellular expansion- exact molecular role unclear Mucosa-associated Cleaves after arginine Type of cysteine protease; likely acts both lymphoid tissue residues as a scaffold and proteolytically active (MALT1) enzyme in the CBM-dependent signaling pathway Tryptase Targets: angiotensin I, Type of mast cell-specific serine protease; fibrinogen, prourokinase, trypsin-like; resistant to inhibition by TGFβ; preferentially macromolecular protease inhibitors cleaves proteins after expressed in mammals due to their lysine or arginine tetrameric structure, with all sites facing residues narrow central pore; also associated with inflammation Associated with inflammation: Thrombin Targets: FGF-2, Type of serine protease; modulates HB-EGF, Osteo-pontin, activity of vascular growth factors, PDGF, VEGF chemokines and extracellular proteins; strengthens VEGF-induced proliferation; induces cell migration; angiogenic factor; regulates hemostasis Chymase Exhibit chymotrypsin- Type of mast cell-specific serine protease like specificity, cleaving proteins after aromatic amino acid residues Carboxypeptidase A Cleaves amino acid Type of zinc-dependent metalloproteinase (MC-CPA) residues from C-terminal end of peptides and proteins Kallikreins Targets: high molecular Type of serine protease; modulate weight relaxation response; contribute to kininogen, pro-urokinase inflammatory response; fibrin degradation Elastase Targets: E-cadherin, GM- Type of neutrophil serine protease; CSF, IL-1, IL-2, IL-6, degrades ECM components; regulates IL8, p38^(MAPK), TNFα, VE- inflammatory response; activates pro- cadherin apoptotic signaling Cathepsin G Targets: EGF, ENA-78, Type of serine protease; degrades ECM IL-8, MCP-1, MMP-2, components; chemo-attractant of MT1-MMP, leukocytes; regulates inflammatory PAI-1, RANTES, TGFβ response; promotes apoptosis TNFα PR-3 Targets: ENA-78, IL-8, Type of serine protease; promotes IL-18, JNK, p38^(MAPK), inflammatory response; activates pro- TNFα apoptotic signaling Granzyme M (grM) Cleaves after Met and Type of serine protease; only expressed in other long, unbranched NK cells hydrophobic residues Calpains Cleave between Arg and Family of cysteine proteases; calcium- Gly dependent; activation is involved in the process of numerous inflammation- associated diseases

?TABLE 1a Exemplary Proteases and Protease Recognition Sequences Cleavage SEQ  Domain ID Protease Sequence NO: MMP7 KRALGLPG 3 MMP7 (DE)8RPLALWRS(DR)8 4 MMP9 PR(S/T)(L/I)(S/T) 5 MMP9 LEATA 6 MMP11 GGAANLVRGG 7 MMP14 SGRIGFLRTA 8 MMP PLGLAG 9 MMP PLGLAX 10 MMP PLGC(me)AG 11 MMP ESPAYYTA 12 MMP RLQLICL 13 MMP RLQLKAC 14 MMP2, MMP9, MMP14 EP(Cit)G(Hof)YL 15 Urokinase plasminogen SGRSA 16 activator (uPA) Urokinase plasminogen DAFK 17 activator (uPA) Urokinase plasminogen GGGRR 18 activator (uPA) Lysosomal Enzyme GFLG 19 Lysosomal Enzyme ALAL 20 Lysosomal Enzyme FK 21 Cathepsin B NLL 22 Cathepsin D PIC(Et)FF 23 Cathepsin K GGPRGLPG 24 Prostate Specific HSSKLQ 25 Antigen Prostate Specific HSSKLQL 26 Antigen Prostate Specific HSSICLQEDA 27 Antigen Herpes Simplex LVLASSSFGY 28 Virus Protease HIV Protease GVSQNYPIVG 29 CMV Protease GVVQASCRLA 30 Thrombin F(Pip)RS 31 Thrombin DPRSFL 32 Thrombin PPRSFL 33 Caspase-3 DEVD 34 Caspase-3 DEVDP 35 Caspase-3 KGSGDVEG 36 Interleukin 1β GWEHDG 37 converting enzyme Enterokinase EDDDDKA 38 FAP KQEQNPGST 39 Kallikrein 2 GKAFRR 40 Plasmin DAFK 41 Plasmin DVLK 42 Plasmin DAFK 43 TOP ALLLALL 44

Provided herein are pharmaceutical compositions comprising polypeptide sequences. As with all peptides, polypeptides, and proteins, including fragments thereof, it is understood that additional modifications in the amino acid sequence of the chimeric polypeptides (amino acid sequence variants) can occur that do not alter the nature or function of the peptides, polypeptides, or proteins. Such modifications include conservative amino acid substitutions and are discussed in greater detail below.

The compositions provided herein have a desired function. The compositions are comprised of at least a cytokine polypeptide, such as IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IFNα, or IFNγ, or a chemokine, such as CXCL10, CCL19, CCL20, CCL21, a blocking moiety, e.g. a steric blocking polypeptide, and an optional serum half-life extension element, and an optional targeting polypeptide, with one or more linkers connecting each polypeptide in the composition. The first polypeptide, e.g., an IL-2 mutein, is provided to be an active agent. The blocking moiety is provided to block the activity of the interleukin. The linker polypeptide, e.g., a protease cleavable polypeptide, is provided to be cleaved by a protease that is specifically expressed at the intended target of the active agent. Optionally, the blocking moiety blocks the activity of the first polypeptide by binding the interleukin polypeptide. In some embodiments, the blocking moiety, e.g. a steric blocking peptide, is linked to the interleukin via a protease-cleavable linker which is cleaved at the site of action (e.g. by inflammation-specific or tumor-specific proteases) releasing the cytokine full activity at the desired site.

The protease cleavage site may be a naturally occurring protease cleavage site or an artificially engineered protease cleavage site. The artificially engineered protease cleavage site can be cleaved by more than one protease specific to the desired environment in which cleavage will occur, e.g. a tumor. The protease cleavage site may be cleavable by at least one protease, at least two proteases, at least three proteases, or at least four proteases.

In some embodiments, the linker comprises glycine-glycine, a sortase-recognition motif, or a sortase-recognition motif and a peptide sequence (Gly₄Ser)_(n) (SEQ ID NO.: 443) or (Gly₃Ser)_(n), (SEQ ID NO.: 444), wherein n is 1, 2, 3, 4 or 5. In one embodiment, the sortase-recognition motif comprises a peptide sequence LPXTG (SEQ ID NO.: 442), where X is any amino acid. In one embodiment, the covalent linkage is between a reactive lysine residue attached to the C-terminal of the cytokine polypeptide and a reactive aspartic acid attached to the N-terminal of the blocking or other moiety. In one embodiment, the covalent linkage is between a reactive aspartic acid residue attached to the N-terminal of the cytokine polypeptide and a reactive lysine residue attached to the C-terminal of the blocking or other moiety.

Cleavage and Inducibility

As described herein, the activity of the cytokine polypeptide the context of the fusion protein is attenuated, and protease cleavage at the desired site of activity, such as in a tumor microenvironment, releases a form of the cytokine from the fusion protein that is much more active as a cytokine receptor agonist than the fusion protein. For example, the cytokine-receptor activating (agonist) activity of the fusion polypeptide can be at least about 10×, at least about 50×, at least about 100×, at least about 250×, at least about 500×, or at least about 1000× less than the cytokine receptor activating activity of the cytokine polypeptide as a separate molecular entity. The cytokine polypeptide that is part of the fusion protein exists as a separate molecular entity when it contains an amino acid that is substantially identical to the cytokine polypeptide and does not substantially include additional amino acids and is not associated (by covalent or non-covalent bonds) with other molecules. If necessary, a cytokine polypeptide as a separate molecular entity may include some additional amino acid sequences, such as a tag or short sequence to aid in expression and/or purification.

In other examples, the cytokine-receptor activating (agonist) activity of the fusion polypeptide is at least about 10×, at least about 50×, at least about 100×, at least about 250×, at least about 500×, or about 1000× less than the cytokine receptor activating activity of the polypeptide that contains the cytokine polypeptide that is produced by cleavage of the protease cleavable linker in the fusion protein. In other words, the cytokine receptor activating (agonist) activity of the polypeptide that contains the cytokine polypeptide that is produced by cleavage of the protease cleavable linker in the fusion protein is at least about 10×, at least about 50×, at least about 100×, at least about 250×, at least about 500×, or at least about 1000× greater than the cytokine receptor activating activity of the fusion protein.

Polypeptide Variants and Amino Acid Substitutions

The polypeptides described herein can include components (e.g., the cytokine, the blocking moiety) that have the same amino acid sequence of the corresponding naturally occurring protein (e.g., IL-2, IL-15, HSA) or can have an amino acid sequence that differs from the naturally occurring protein so long as the desired function is maintained. It is understood that one way to define any known modifications and derivatives or those that might arise, of the disclosed proteins and nucleic acids that encode them is through defining the sequence variants in terms of identity to specific known reference sequences. Specifically disclosed are polypeptides and nucleic acids which have at least, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 percent identity to the chimeric polypeptides provided herein. For example, provided are polypeptides or nucleic acids that have at least, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 percent identity to the sequence of any of the nucleic acids or polypeptides described herein. Those of skill in the art readily understand how to determine the identity of two polypeptides or two nucleic acids. For example, the identity can be calculated after aligning the two sequences so that the identity is at its highest level.

Another way of calculating identity can be performed by published algorithms. Optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman Adv. Appl. Math. 2:482 (1981), by the identity alignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by inspection.

The same types of identity can be obtained for nucleic acids by, for example, the algorithms disclosed in Zuker, Science 244:48-52 (1989); Jaeger et al., Proc. Natl. Acad. Sci. USA 86:7706-7710 (1989); Jaeger et al., Methods Enzymol. 183:281-306 (1989), which are herein incorporated by reference for at least material related to nucleic acid alignment. It is understood that any of the methods typically can be used and that in certain instances the results of these various methods may differ, but the skilled artisan understands if identity is found with at least one of these methods, the sequences would be said to have the stated identity, and be disclosed herein.

Protein modifications include amino acid sequence modifications. Modifications in amino acid sequence may arise naturally as allelic variations (e.g., due to genetic polymorphism), may arise due to environmental influence (e.g., by exposure to ultraviolet light), or may be produced by human intervention (e.g., by mutagenesis of cloned DNA sequences), such as induced point, deletion, insertion and substitution mutants. These modifications can result in changes in the amino acid sequence, provide silent mutations, modify a restriction site, or provide other specific mutations. Amino acid sequence modifications typically fall into one or more of three classes: substitutional, insertional or deletional modifications. Insertions include amino and/or carboxyl terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions ordinarily will be smaller insertions than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues. Deletions are characterized by the removal of one or more amino acid residues from the protein sequence. Typically, no more than about from 2 to 6 residues are deleted at any one site within the protein molecule. Amino acid substitutions are typically of single residues, but can occur at a number of different locations at once; insertions usually will be on the order of about from 1 to 10 amino acid residues; and deletions will range about from 1 to 30 residues. Deletions or insertions preferably are made in adjacent pairs, i.e. a deletion of 2 residues or insertion of 2 residues. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final construct. The mutations must not place the sequence out of reading frame and preferably will not create complementary regions that could produce secondary mRNA structure. Substitutional modifications are those in which at least one residue has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with the following Table 2 and are referred to as conservative substitutions.

?TABLE 2 Exemplary amino acid substitutions Amino Acid Exemplary Substitutions Ala Ser, Gly, Cys Arg Lys, Gln, Met, Ile Asn Gln, His, Glu, Asp Asp Glu, Asn, Gln Cys Ser, Met, Thr Gln Asn, Lys, Glu, Asp Glu Asp, Asn, Gln Gly Pro, Ala His Asn, Gln Ile Leu, Val, Met Leu Ile, Val, Met Lys Arg, Gln, Met, Ile Met Leu, Ile, Val Phe Met, Leu, Tyr, Trp, His Ser Thr, Met, Cys Thr Ser, Met, Val Trp Tyr, Phe Tyr Trp, Phe, His Val Ile, Leu, Met

Modifications, including the specific amino acid substitutions, are made by known methods. For example, modifications are made by site specific mutagenesis of nucleotides in the DNA encoding the polypeptide, thereby producing DNA encoding the modification, and thereafter expressing the DNA in recombinant cell culture. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, for example M13 primer mutagenesis and PCR mutagenesis.

Modifications can be selected to optimize binding. For example, affinity maturation techniques can be used to alter binding of the scFv by introducing random mutations inside the complementarity determining regions (CDRs). Such random mutations can be introduced using a variety of techniques, including radiation, chemical mutagens or error-prone PCR. Multiple rounds of mutation and selection can be performed using, for example, phage display.

The disclosure also relates to nucleic acids that encode the chimeric polypeptides described herein, and to the use of such nucleic acids to produce the chimeric polypeptides and for therapeutic purposes. For example, the invention includes DNA and RNA molecules (e.g., mRNA, self-replicating RNA) that encode a chimeric polypeptide and to the therapeutic use of such DNA and RNA molecules.

Exemplary Compositions

Exemplary fusion proteins of the invention combine the above described elements in a variety of orientations. The orientations described in this section are meant as examples and are not to be considered limiting.

In some embodiments, the fusion protein comprises a cytokine, a blocking moiety and a half-life extension element. In some embodiments, the cytokine is positioned between the half-life extension element and the blocking moiety. In some embodiments, the cytokine is N-terminal to the blocking moiety and the half-life extension element. In some such embodiments, the cytokine is proximal to the blocking moiety; in some such embodiments, the cytokine is proximal to the half-life extension element. At least one protease-cleavable linker must be included in all embodiments, such that the cytokine may be active upon cleavage. In some embodiments, the cytokine is C-terminal to the blocking moiety and the half-life extension element. Additional elements may be attached to one another by a cleavable linker, a non-cleavable linker, or by direct fusion.

In some embodiments, the blocking domains used are capable of extending half-life, and the cytokine is positioned between two such blocking domains. In some embodiments, the cytokine is positioned between two blocking domains, one of which is capable of extending half-life.

In some embodiments, two cytokines are included in the same construct. In some embodiments, the cytokines are connected to two blocking domains each (three in total in one molecule), with a blocking domain between the two cytokine domains. In some embodiments, one or more additional half-life extension domains may be included to optimize pharmacokinetic properties. In some cases, it is beneficial to include two of the same cytokine to facilitate dimerization. An example of a cytokine that works as a dimer is IFN.

In some embodiments, three cytokines are included in the same construct. In some embodiments, the third cytokine may function to block the other two in place of a blocking domain between the two cytokines.

Preferred half-life extension elements for use in the fusion proteins are human serum albumin (HSA), an antibody or antibody fragment (e.g., scFV, dAb) which binds serum albumin, a human or humanized IgG, or a fragment of any of the foregoing. In some preferred embodiments, the blocking moiety is human serum albumin (HSA), or an antibody or antibody fragment which binds serum albumin, an antibody which binds the cytokine and prevents activation of binding or activation of the cytokine receptor, another cytokine, or a fragment of any of the foregoing. In preferred embodiments comprising an additional targeting domain, the targeting domain is an antibody which binds a cell surface protein which is enriched on the surface of cancer cells, such as EpCAM, FOLR1, and Fibronectin.

In embodiments, the fusion protein can contain an IL-2 polypeptide. The fusion protein containing an IL-2 polypeptide can comprise or consist of the amino acid sequence of any one of SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608 and 636-646. The fusion proteins disclosed as SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, and 636-646 are also referred to herein as ACP289-ACP292, ACP296-ACP302, WW0301, ACP304-ACP306, ACP309-ACP313, WW0353, ACP414, ACP336-ACP398, WW0472-WW0477, ACP406-ACP426, ACP439-ACP447, ACP451-ACP471, WW0729, WW0734-WW0792, ACP101, ACP293-ACP295, ACP316-ACP335, ACP427-ACP438, and ACP448-ACP450. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 272. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 286. The fusion protein can comprise the amino acid sequence of SEQ ID NO:362. The fusion protein can comprise the amino acid sequence of SEQ ID NO:336. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 348. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 363. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 580.

In embodiments, the fusion protein can contain an IL-12 polypeptide. The fusion protein containing an IL-12 polypeptide can comprise or consist of the amino acid sequence of any one of SEQ ID NOs. 368-371, 434-440, 453-519, or 523-538. The fusion proteins disclosed as SEQ ID NOs. 368-371, 434-440, 453-519, or 523-538 are referred to herein as ACP240-ACP245, ACP247, ACP285-ACP288, WW0641, WW0649-WW0652, WW0662-WW0725, WW0765-WW0772, and WW0796-WW0803. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO:459. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 466. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 484. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 506.

In embodiments, the fusion protein contains an IFN (e.g., IFNgamma, IFNalpha, IFNbeta) polypeptide. In some examples the IFN polypeptide is an IFNalpha or an IFNbeta. The fusion protein containing an IFN polypeptide can comprise or consist of the amino acid sequence of SEQ ID NOs. 421-430, and 539-578. The fusion proteins disclosed as SEQ ID NOs. 421-430, and 539-578 can be referred to herein as ACP200-ACP209, WW0644-WW0648, WW0781-WW0786, WW0815-WW0822, WW0831-WW0834, WW0737-WW0748, and WW0787-WW0790. For example, the fusion protein can comprise the amino acid sequence of SEQ ID NO: 421. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 428. The fusion protein can comprise the amino acid sequence of 541. The fusion protein can comprise the amino acid sequence of SEQ IND NO: 558. The fusion protein can comprise the amino acid sequence of SEQ ID NO: 577.

In some aspects, the fusion polypeptide disclosed herein can be covalently or non-covalently bonded to a second polypeptide chain. For example, a fusion polypeptide can dimerize (i.e. form a dimer) or a portion of a fusion polypeptide may associate with another polypeptide, for example, to form a functional binding site for a cytokine polypeptide or serum albumin. In certain embodiments, the second polypeptide chain and the blocking moiety on the fusion polypeptide are complementary and together form a functional binding site that has specificity for the cytokine polypeptide contained in the fusion polypeptide. Exemplary functional binding sites that can be formed by the blocking moiety of the fusion polypeptide and a complimentary second polypeptide include antigen binding sites of antibodies, such as a Fab fragment of an antibody or a portion thereof. For example, one chain of a Fab that binds the cytokine can be the blocking moiety of the fusion polypeptide, e.g., a VH-CH1, and the complementary VL-CL can be part of the second polypeptide. In such situations, the blocking moiety of the fusion protein i.e., VH-CH1 and the second polypeptide that comprises the complementary VL-CL, can associate to form a functional binding site with specificity for the cytokine polypeptide contained within the fusion protein (e.g., IL-2, IL-12, IFNalpha, IFNbeta) and attenuates cytokine polypeptide activity. At least a portion of the blocking moiety can be on the second polypeptide chain can comprise at least a portion of the blocking moiety that associates with the blocking moiety on the fusion polypeptide.

In embodiments, the fusion protein containing an IL-2 cytokine polypeptide can be bonded covalently or noncovalently to a second polypeptide chain. The second polypeptide chain can contain an antibody light chain VL-CL that comprises or consist of the amino acid sequence of SEQ ID NO: 263, 264, or 333. Such a second polypeptide can bond with a complimentary VH-CH1 polypeptide contained within the fusion protein, e.g., as contained within SEQ ID NOS: 362, 363, 325, 286, 579, 581, or 582. The second polypeptide chain disclosed as SEQ ID NOs. 263, 264, and 333 can be referred herein as WW0523 (ACP381), WW0524 (ACP382), or WW0556 (ACP414).

In embodiments, the fusion polypeptide can comprise or consist of the amino acid sequence of SEQ ID NOs. 362, 363, 325, 286, 579, 581, or 582 and the second polypeptide chain can comprise or consist of the amino acid sequence of SEQ ID NOs: 263, 264, or 333. The fusion polypeptide disclosed as SEQ ID NOs. 362, 363, 325, 286, 579, 581, or 582 can be referred to as WW0520 (ACP378), WW0521 (ACP379), WW0548 (ACP406), WW0621 (ACP457), WW0729, WW0735, or WW0736, and the second polypeptide chain disclosed as SEQ ID NOs. 263, 264, and 333 can be referred herein as WW0523 (ACP381), WW0524 (ACP382), or WW0556 (ACP414).

For example, the fusion protein can comprise or consist the amino acid sequence of SEQ ID NO: 362 and the second polypeptide chain can comprise or consist the amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist the amino acid sequence of SEQ ID NO: 362 and the second polypeptide chain can comprise or consist the amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist the amino acid sequence of SEQ ID NO: 362 and the second polypeptide chain can comprise or consist the amino acid sequence of SEQ ID NO: 333. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 363 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID No. 363 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 363 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 333. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 325 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 325 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 333. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 325 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 286 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 286 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 286, and the second polypeptide can comprise or consist of an amino acid sequence of SEW ID NO: 333. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 579 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 579 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of an amino acid sequence of SEQ ID NO: 579 and the second polypeptide chain can comprise or consist of an amino acid sequence of SEQ ID NO: 233. For example, the fusion protein can comprise or consist of SEQ ID NO: 581 and the second polypeptide chain can comprise or consist of SEQ ID NO.: 263. For example, the fusion protein can comprise or consist of SEQ ID NO: 581 and the second polypeptide chain can comprise or consist of SEQ ID NO.: 264. For example, the fusion protein can comprise or consist of SEQ ID NO: 581 and the second polypeptide chain can comprise or consist of SEQ ID NO.: 333. For example, the fusion protein can comprise or consist of SEQ ID NO: 582 and the second polypeptide chain can comprise or consist of SEQ ID NO: 263. For example, the fusion protein can comprise or consist of SEQ ID NO: 582 and the second polypeptide chain can comprise or consist of SEQ ID NO: 264. For example, the fusion protein can comprise or consist of SEQ ID NO: 582 and the second polypeptide chain can comprise or consist of SEQ ID NO: 333.

Methods of Treatment and Pharmaceutical Compositions

This disclosure also relates to pharmaceutical compositions that comprise one or more fusion proteins as disclosed herein, optionally in combination with another therapeutic agent, which are preferably immunomodulators or anti-cancer agents. The disclosure also relates to the use of such pharmaceutical compositions, and one or more fusion proteins, optionally in combination with another therapeutic agent in treatment of cancers.

The therapeutic combinations disclosed herein can comprise, for example, a fusion protein containing an IL-2 polypeptide, a fusion protein containing an IL-12 polypeptide, or a fusion protein containing an IFN polypeptide. Therapy can be provided using two or more fusion proteins. For example, the therapeutic combination can comprise a fusion protein containing an IL-2 polypeptide and a fusion protein containing an IL-12 polypeptide, a fusion protein containing an IL-2 polypeptide and a fusion protein containing an IFN polypeptide, a fusion protein containing an IL-12 polypeptide and a fusion protein containing an IFN polypeptide.

The therapeutic combinations disclosed herein can comprise a fusion polypeptide cytokine polypeptide [A], a blocking moiety [D], optionally a half-life extension moiety [H], and a protease-cleavable polypeptide linker, wherein the cytokine polypeptide and the blocking moiety and the optional half-life extension element when present are operably linked by the protease-cleavable polypeptide linker and the fusion polypeptide has attenuated cytokine receptor activating activity, wherein the cytokine-receptor activating activity of the fusion polypeptide is at least about 10× less than the cytokine receptor activating activity of the polypeptide that contains the cytokine polypeptide that is produced by cleavage of the protease cleavable linker. the fusion polypeptide has the formula:

[A]-[L1]-[H]-[L2]-[D]  (I);

[D]-[L2]-[H]-[L1]-[A]  (II);

[A]-[L1]-[D]-[L2]-[H]  (III);

[H]-[L2]-[D]-[L1]-[A]  (IV);

[H]-[L1]-[A]-[L2′]-[D]  (V);

[D]-[L1]-[A]-[L2′]-[H]  (VI);

wherein [A] is a cytokine polypeptide, [D] is a blocking moiety, [H] is a half-life extension moiety, [L1] is a protease-cleavable polypeptide linker, [L2] is an polypeptide linker that is optionally protease-cleavable, and [L2′] is a protease-cleavable polypeptide linker. The therapeutic compositions can comprise a second fusion polypeptide comprising at least one of each of: a second cytokine polypeptide [A], a blocking moiety [D]optionally a half-life extension element [H]; and a protease-cleavable polypeptide linker [L]; wherein the cytokine polypeptide and the cytokine blocking moiety and the optional half-life extension element when present are operably linked by the protease-cleavable polypeptide linker and the fusion polypeptide has attenuated cytokine receptor activating activity, wherein the cytokine-receptor activating activity of the fusion polypeptide is at least about 10× less than the cytokine receptor activating activity of the polypeptide that contains the cytokine polypeptide that is produced by cleavage of the protease cleavable linker. The second fusion polypeptide can have the formula:

[A]-[L1]-[H]-[L2]-[D]  (I);

[D]-[L2]-[H]-[L1]-[A]  (II);

[A]-[L1]-[D]-[L2]-[H]  (III);

[H]-[L2]-[D]-[L1]-[A]  (IV);

[H]-[L1]-[A]-[L2′]-[D]  (V);

[D]-[L1]-[A]-[L2′]-[H]  (VI);

wherein [A] is a cytokine polypeptide, [D] is a blocking moiety, [H] is a half-life extension moiety, [L1] is a protease-cleavable polypeptide linker, [L2] is an polypeptide linker that is optionally protease-cleavable, and [L2′] is a protease-cleavable polypeptide linker.

The therapeutic combinations disclosed herein can comprise a first fusion protein comprising an amino acid selected from the group consisting of SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, 636-646, 368-371, 434-440, 453-519, 523-538, 421-430, and 539-578 and a second fusion protein comprising an amino acid sequence selected from the group consisting of selected from the group consisting of SEQ ID NOs. 257-300,302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, 636-646, 368-371, 434-440, 453-519, 523-538, 421-430, and 539-578. It is preferred that the first fusion protein and the second fusion protein are different. In some preferred embodiments, the therapeutic combination comprises a first fusion protein comprising an amino acid sequence selected from SEQ ID NO: 257-300,302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, 636-646 and a second fusion protein comprising an amino acid sequence selected from SEQ ID NO: 368-371, 434-440, 453-519, 523-538, 421-430, and 539-578. In some preferred embodiments, the therapeutic combination comprises a first fusion proteins comprising an amino acid sequence selected from SEQ ID NO: 368-371, 434-440, 453-519, or 523-538 and a second fusion protein comprising an amino acid sequence selected from SEQ ID NO: 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 636-646, 579-608, 421-430, and 539-578. In some preferred embodiments, the therapeutic combination comprises a first fusion protein comprising an amino acid sequence selected from SEQ ID NO: 421-430, and 539-578 and a second fusion protein comprising an amino acid sequence selected from SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, 636-646, 368-371, 434-440, 453-519, 523-538, or combinations thereof.

The therapeutic combination disclosed herein can comprise a first fusion protein that is covalently or non-covalently bonded to a second polypeptide chain and a therapeutic agent. The therapeutic combination can comprise (i) a fusion polypeptide comprising an amino acid sequence selected from SEQ ID NOs. 362, 363, 325, 286, 579, 581, or 582 and a second polypeptide chain comprising the amino acid sequence of SEQ ID NOs: 263, 264, or 333, and (ii) a second therapeutic agent, wherein the second therapeutic agent is a second fusion polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs. 257-300,302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, 636-646, 368-371, 434-440, 453-519, 523-538, 421-430, 539-578, or combinations thereof. It is preferred that the first fusion protein and the second fusion protein are not the same.

In embodiments, the therapeutic combination can comprise an additional therapeutic agent (e.g., one, two, three, four, five, or more therapeutic agents). In embodiments, the therapeutic combination can comprise 2 or more fusion proteins and one or more therapeutic agents, preferably agents for treating cancer.

Other exemplary therapeutic agents include, but are not limited to chemotherapeutic agents (e.g., Adriamycin, Cerubidine, Bleomycin, Alkeran, Velban, Oncovin, Fluorouracil, Thiotepa, Methotrexate, Bisantrene, Noantrone, Thiguanine, Cytaribine, Procarabizine), immuno-oncology agents (e.g., anti-PD-L1, anti-CTLA4, anti-PD-1, anti-CD47, anti-GD2, VEGF inhibitor), antibody-drug conjugates, cellular therapies (e.g, CAR-T, T-cell therapy), oncolytic viruses, radiation therapy and/or small molecules.

Non-limiting examples of anti-cancer agents that can be used include acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer, carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1 interferon alpha-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur, talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinzolidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

Accordingly, this disclosure relates to a therapeutic combination of any of the fusions proteins disclosed herein (e.g., fusion proteins that comprise an IL-2 polypeptide, and IL-12 polypeptide or an IFN polypeptide) in combination with a chemotherapeutic agent, such as Adriamycin, Cerubidine, Bleomycin, Alkeran, Velban, Oncovin, Fluorouracil, Thiotepa, Methotrexate, Bisantrene, Noantrone, Thiguanine, Cytaribine, Procarabizine. This disclosure relates to a therapeutic combination of any of the fusions proteins disclosed herein (e.g., fusion proteins that comprise an IL-2 polypeptide, and IL-12 polypeptide or an IFN polypeptide) in combination with an antibody-drug conjugate. A variety of antibody drug conjugates that are suitable for use in cancer therapy are well known and typically include an antibody that binds to a cellular antigen that is preferentially express or expressed at high levels on tumor cells, and a cytotoxic drug. This disclosure relates to a therapeutic combination of any of the fusion proteins disclosed herein (e.g., fusion proteins that comprise an IL-2 polypeptide, and IL-12 polypeptide, or an IFN polypeptide) in combination with a cellular therapy, such as CAR-T or T-cell therapy. The disclosure relates to a therapeutic combination of the fusion proteins disclosed herein (e.g., fusion proteins that comprise an IL-2 polypeptide, and IL-12 polypeptide, or an IFN polypeptide) in combination with an oncolytic virus. Exemplary oncolytic viruses include, oncolytic adenoviruses, type 1 herpes simplex virus (HSV), polioviruses, measles virus (MV), Newcastle disease virus (NDV), reoviruses, vesicular stomatitis virus (VSV), and Zika virus. This disclosure relates to a therapeutic combination of any of the fusion proteins disclosed herein (e.g., fusion proteins that comprise an IL-2 polypeptide, and IL-12 polypeptide, or an IFN polypeptide) in combination with radiation therapy, such an external beam radiation or internal therapy radiation therapy.

This disclosure relates to a therapeutic combination of any of the fusion proteins disclosed herein (e.g., fusion proteins that comprise an IL-2 polypeptide, and IL-12 polypeptide, or an IFN polypeptide) in combination with cytokines (e.g., IL-2, IL-15), signal induction inhibitors (e.g., BRAF inhibitors or MEK inhibitors), checkpoint inhibitors (e.g., PDL-1, PD-1, CTLA-4), c-met inhibitors, kinase inhibitors (e.g., VGEF inhibitors), a proteasome inhibitor, mTOR inhibitor, angiogenesis inhibitor. In embodiments, any one of the fusion proteins disclosed herein (e.g., fusion proteins that comprise an IL-2 polypeptide, and IL-12 polypeptide, or an IFN polypeptide) can be combined with an anti-PD-L1 agent or an anti-PD-1 agent. Exemplary PD-1 and/or PD-L1 inhibitors include, but are not limited to Spartalizumab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, Dostarlimab, INCMGA00012, AMP-224, and AMP-514). In embodiments, a fusion protein comprising the amino acid sequence selected from SEQ ID NO: 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, 636-646, 368-371, 434-440, 453-519, 523-538, 421-430, and 539-578 can be combined with a check-point inhibitor, such as PDL-1, PD-1, or CTL-4.

Further provided are methods of treating a subject with or at risk of developing an of a disease or disorder, such as proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, or graft-versus-host disease. The methods disclosed herein are preferably used to treat a subject having cancer. The methods administering to a subject in need thereof an effective amount of a fusion protein as disclosed herein that is typically administered as a pharmaceutical composition. In some embodiments, the method further comprises selecting a subject with or at risk of developing such a disease or disorder. The pharmaceutical composition preferably comprises a blocked cytokine, fragment, variant, subunit, or mutein thereof that is activated at a site of inflammation or a tumor. In one embodiment, the chimeric polypeptide comprises a cytokine polypeptide, fragment or mutein thereof and a serum half-life extension element. In another embodiment, the chimeric polypeptide comprises a cytokine polypeptide, variant, subunit, fragment or mutein thereof and a blocking moiety, e.g. a steric blocking polypeptide, wherein the steric blocking polypeptide is capable of sterically blocking the activity of the cytokine polypeptide, fragment or mutein thereof. In another embodiment, the chimeric polypeptide comprises a cytokine polypeptide, fragment or mutein thereof, a blocking moiety, and a serum half-life extension element.

Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair. Inflammation can occur from infection, as a symptom or a disease, e.g., cancer, atherosclerosis, allergies, myopathies, HIV, obesity, or an autoimmune disease. An autoimmune disease is a chronic condition arising from an abnormal immune response to a self-antigen. Autoimmune diseases that may be treated with the polypeptides disclosed herein include but are not limited to lupus, celiac disease, diabetes mellitus type 1, Graves disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.

The pharmaceutical composition can comprise one or more protease-cleavable linker sequences. The linker sequence serves to provide flexibility between polypeptides, such that each polypeptide is capable of inhibiting the activity of the first polypeptide. The linker sequence can be located between any or all of the cytokine polypeptide, fragment or mutein thereof, the blocking moiety, and serum half-life extension element. Optionally, the composition comprises, two, three, four, or five linker sequences. The linker sequence, two, three, or four linker sequences can be the same or different linker sequences. In one embodiment, the linker sequence comprises GGGGS (SEQ ID NO.: 449), GSGSGS (SEQ ID NO.: 450), or G(SGGG)₂SGGT (SEQ ID NO.: 451). In another embodiment, the linker comprises a protease-cleavable sequence selected from group consisting of HSSKLQ (SEQ ID NO.: 25), GPLGVRG (SEQ ID NO.: 445), IPVSLRSG (SEQ ID NO.: 446), VPLSLYSG (SEQ ID NO.: 447), and SGESPAYYTA (SEQ ID NO.: 448).

In some embodiments, the linker is cleaved by a protease selected from the group consisting of a kallikrein, thrombin, chymase, carboxypeptidase A, cathepsin G, an elastase, PR-3, granzyme M, a calpain, a matrix metalloproteinase (MMP), a plasminogen activator, a cathepsin, a caspase, a tryptase, or a tumor cell surface protease.

Suitable linkers can be of different lengths, such as from 1 amino acid (e.g., Gly) to 20 amino acids, from 2 amino acids to 15 amino acids, from 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 amino acids.

Further provided are methods of treating a subject with or at risk of developing cancer. The methods comprise administering to the subject in need thereof an effective amount of a chimeric polypeptide (a fusion protein) as disclosed herein that is typically administered as a pharmaceutical composition. In some embodiments, the method further comprises selecting a subject with or at risk of developing cancer. The pharmaceutical composition preferably comprises a blocked cytokine, fragment or mutein thereof that is activated at a tumor site.

The methods disclosed herein can be used for any suitable cancer including, hematological malignancy, solid tumors, sarcomas, carcinomas, and other solid and non-solid tumors. Illustrative suitable cancers include, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer, bronchial tumor, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fingoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, nasal cavity and par nasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytomas, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, renal pelvis and ureter cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, stomach cancer, T-cell lymphoma, teratoid tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms tumor.

Preferably, the tumor is a solid tumor. Colon cancer, lung cancer, melanoma, sarcoma, renal cell carcinoma, and breast cancer are of particular interest.

The method can further involve the administration of one or more additional agents to treat cancer, such as one or more cytokine fusion proteins described herein, chemotherapeutic agents (e.g., Adriamycin, Cerubidine, Bleomycin, Alkeran, Velban, Oncovin, Fluorouracil, Thiotepa, Methotrexate, Bisantrene, Noantrone, Thiguanine, Cytaribine, Procarabizine), immuno-oncology agents (e.g., anti-PD-L1, anti-CTLA4, anti-PD-1, anti-CD47, anti-GD2, VEGF inhibitor), cellular therapies (e.g, CAR-T, T-cell therapy), oncolytic viruses, radiation therapy and the like.

In embodiments, the fusion proteins described herein, can be administered with one or more additional cytokine fusion proteins that are inducible. For example, a fusion protein containing an IL-2 polypeptide, as described herein, may be administered with fusion protein containing an IL-12 polypeptide, an IFN polypeptide, a different IL-2 polypeptide or a combinations thereof. A fusion protein containing an IL-12 polypeptide, as described herein, may be administered with a fusion protein containing an IL-2 polypeptide, an IFN polypeptide, a different IL-12 polypeptide or a combinations thereof. A fusion protein containing an IFN polypeptide, as described herein, may be administered with a fusion protein containing anIL-2 polypeptide, an IL-12 polypeptide, an different IFN polypeptide, or a combinations thereof.

In some preferred embodiments, a first fusion protein comprising the amino acid sequence of any one of SEQ ID NOS: 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, and 636-646 can be administered with a second different fusion protein comprising an amino acid sequence of any one of SEQ ID NOs. 368-371, 434-440, 453-519, 523-538, 421-430, and 539-578. In some preferred embodiments, a first fusion proteins comprising the amino acid sequence of any one of 368-371, 434-440, 453-519, or 523-538 can be administered with a second different fusion protein comprising an amino acid sequence of any one of SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, 636-646, 421-430, and 539-578. In some preferred embodiments, a first fusion protein comprising the amino acid sequence of any one of SEQ ID NOs. 421-430, and 539-578 can be administered with a second different fusion protein comprising the amino acid sequence of any one of SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, 636-646, 368-371, 434-440, 453-519, 523-538, or combinations thereof.

Further exemplary agents that can be administered in combination with one or more inducible cytokine fusion proteins described herein include, but are not limited to cytokines (e.g., IL-2, IL-15), signal induction inhibitors (e.g., BRAF inhibitors or MEK inhibitors), checkpoint inhibitors (e.g., PDL-1, PD-1, CTLA-4), c-met inhibitors, kinase inhibitors (e.g., VGEF inhibitors), a proteasome inhibitor, mTOR inhibitor, angiogenesis inhibitor.

A preferred immuno-oncology agent is an anti-PD-L1 agent or an anti-PD-1. Exemplary PD-1 and/or PD-L1 inhibitors include, but are not limited to Spartalizumab, Camrelizumab, Sintilimab, Tislelizumab, Toripalimab, Dostarlimab, INCMGA00012, AMP-224, and AMP-514). In embodiments, a fusion protein disclosed as 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, 636-646, 368-371, 434-440, 453-519, 523-538, 421-430, and 539-578 can be administered in combination with a check-point inhibitor, such as PDL-1, PD-1, or CTL-4.

Provided herein are pharmaceutical formulations or compositions containing the chimeric polypeptides and a pharmaceutically acceptable carrier. The herein provided compositions are suitable for administration in vitro or in vivo. By pharmaceutically acceptable carrier is meant a material that is not biologically or otherwise undesirable, i.e., the material is administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical formulation or composition in which it is contained. The carrier is selected to minimize degradation of the active ingredient and to minimize adverse side effects in the subject.

Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy, 21^(st) Edition, David B. Troy, ed., Lippicott Williams & Wilkins (2005). Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic, although the formulate can be hypertonic or hypotonic if desired. Examples of the pharmaceutically-acceptable carriers include, but are not limited to, sterile water, saline, buffered solutions like Ringers solution, and dextrose solution. The pH of the solution is generally about 5 to about 8 or from about 7 to 7.5. Other carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the immunogenic polypeptides. Matrices are in the form of shaped articles, e.g., films, liposomes, or microparticles. Certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered. Carriers are those suitable for administration of the chimeric polypeptides or nucleic acid sequences encoding the chimeric polypeptides to humans or other subjects.

The pharmaceutical formulations or compositions are administered in a number of ways depending on whether local or systemic treatment is desired and on the area to be treated. The compositions are administered via any of several routes of administration, including topically, orally, parenterally, intravenously, intra-articularly, intraperitoneally, intramuscularly, subcutaneously, intracavity, transdermally, intrahepatically, intracranially, nebulization/inhalation, or by installation via bronchoscopy. In some embodiments, the compositions are administered locally (non-systemically), including intratumorally, intra-articularly, intrathecally, etc.

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives are optionally present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

Formulations for topical administration include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners and the like are optionally necessary or desirable.

Compositions for oral administration include powders or granules, suspension or solutions in water or non-aqueous media, capsules, sachets, or tables. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders are optionally desirable.

Optionally, the chimeric polypeptides or nucleic acid sequences encoding the chimeric polypeptides are administered by a vector. There are a number of compositions and methods which can be used to deliver the nucleic acid molecules and/or polypeptides to cells, either in vitro or in vivo via, for example, expression vectors. These methods and compositions can largely be broken down into two classes: viral based delivery systems and non-viral based delivery systems. Such methods are well known in the art and readily adaptable for use with the compositions and methods described herein. Such compositions and methods can be used to transfect or transduce cells in vitro or in vivo, for example, to produce cell lines that express and preferably secrete the encoded chimeric polypeptide or to therapeutically deliver nucleic acids to a subject. The components of the chimeric nucleic acids disclosed herein typically are operably linked in frame to encode a fusion protein.

As used herein, plasmid or viral vectors are agents that transport the disclosed nucleic acids into the cell without degradation and include a promoter yielding expression of the nucleic acid molecule and/or polypeptide in the cells into which it is delivered. Viral vectors are, for example, Adenovirus, Adeno-associated virus, herpes virus, Vaccinia virus, Polio virus, Sindbis, and other RNA viruses, including these viruses with the HIV backbone. Also preferred are any viral families which share the properties of these viruses which make them suitable for use as vectors. Retroviral vectors, in general are described by Coffin et al., Retroviruses, Cold Spring Harbor Laboratory Press (1997), which is incorporated by reference herein for the vectors and methods of making them. The construction of replication-defective adenoviruses has been described (Berkner et al., J. Virol. 61:1213-20 (1987); Massie et al., Mol. Cell. Biol. 6:2872-83 (1986); Haj-Ahmad et al., J. Virol. 57:267-74 (1986); Davidson et al., J. Virol. 61:1226-39 (1987); Zhang et al., BioTechniques 15:868-72 (1993)). The benefit and the use of these viruses as vectors is that they are limited in the extent to which they can spread to other cell types, since they can replicate within an initial infected cell, but are unable to form new infectious viral particles. Recombinant adenoviruses have been shown to achieve high efficiency after direct, in vivo delivery to airway epithelium, hepatocytes, vascular endothelium, CNS parenchyma, and a number of other tissue sites. Other useful systems include, for example, replicating and host-restricted non-replicating vaccinia virus vectors.

The provided polypeptides and/or nucleic acid molecules can be delivered via virus like particles. Virus like particles (VLPs) consist of viral protein(s) derived from the structural proteins of a virus. Methods for making and using virus like particles are described in, for example, Garcea and Gissmann, Current Opinion in Biotechnology 15:513-7 (2004).

The provided polypeptides can be delivered by subviral dense bodies (DBs). DBs transport proteins into target cells by membrane fusion. Methods for making and using DBs are described in, for example, Pepperl-Klindworth et al., Gene Therapy 10:278-84 (2003).

The provided polypeptides can be delivered by tegument aggregates. Methods for making and using tegument aggregates are described in International Publication No. WO 2006/110728.

Non-viral based delivery methods, can include expression vectors comprising nucleic acid molecules and nucleic acid sequences encoding polypeptides, wherein the nucleic acids are operably linked to an expression control sequence. Suitable vector backbones include, for example, those routinely used in the art such as plasmids, artificial chromosomes, BACs, YACs, or PACs. Numerous vectors and expression systems are commercially available from such corporations as Novagen (Madison, Wis.), Clonetech (Pal Alto, Calif.), Stratagene (La Jolla, Calif.), and Invitrogen/Life Technologies (Carlsbad, Calif.). Vectors typically contain one or more regulatory regions. Regulatory regions include, without limitation, promoter sequences, enhancer sequences, response elements, protein recognition sites, inducible elements, protein binding sequences, 5′ and 3′ untranslated regions (UTRs), transcriptional start sites, termination sequences, polyadenylation sequences, and introns. Such vectors can also be used to make the chimeric polypeptides by expression is a suitable host cell, such as CHO cells.

Preferred promoters controlling transcription from vectors in mammalian host cells may be obtained from various sources, for example, the genomes of viruses such as polyoma, Simian Virus 40 (SV40), adenovirus, retroviruses, hepatitis B virus, and most preferably cytomegalovirus (CMV), or from heterologous mammalian promoters, e.g. β-actin promoter or EF1α promoter, or from hybrid or chimeric promoters (e.g., CMV promoter fused to the β-actin promoter). Of course, promoters from the host cell or related species are also useful herein.

Enhancer generally refers to a sequence of DNA that functions at no fixed distance from the transcription start site and can be either 5′ or 3′ to the transcription unit. Furthermore, enhancers can be within an intron as well as within the coding sequence itself. They are usually between 10 and 300 base pairs (bp) in length, and they function in cis. Enhancers usually function to increase transcription from nearby promoters. Enhancers can also contain response elements that mediate the regulation of transcription. While many enhancer sequences are known from mammalian genes (globin, elastase, albumin, fetoprotein, and insulin), typically one will use an enhancer from a eukaryotic cell virus for general expression. Preferred examples are the SV40 enhancer on the late side of the replication origin, the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.

The promoter and/or the enhancer can be inducible (e.g. chemically or physically regulated). A chemically regulated promoter and/or enhancer can, for example, be regulated by the presence of alcohol, tetracycline, a steroid, or a metal. A physically regulated promoter and/or enhancer can, for example, be regulated by environmental factors, such as temperature and light. Optionally, the promoter and/or enhancer region can act as a constitutive promoter and/or enhancer to maximize the expression of the region of the transcription unit to be transcribed. In certain vectors, the promoter and/or enhancer region can be active in a cell type specific manner. Optionally, in certain vectors, the promoter and/or enhancer region can be active in all eukaryotic cells, independent of cell type. Preferred promoters of this type are the CMV promoter, the SV40 promoter, the β-actin promoter, the EF1α promoter, and the retroviral long terminal repeat (LTR).

The vectors also can include, for example, origins of replication and/or markers. A marker gene can confer a selectable phenotype, e.g., antibiotic resistance, on a cell. The marker product is used to determine if the vector has been delivered to the cell and once delivered is being expressed. Examples of selectable markers for mammalian cells are dihydrofolate reductase (DHFR), thymidine kinase, neomycin, neomycin analog G418, hygromycin, puromycin, and blasticidin. When such selectable markers are successfully transferred into a mammalian host cell, the transformed mammalian host cell can survive if placed under selective pressure. Examples of other markers include, for example, the E. coli lacZ gene, green fluorescent protein (GFP), and luciferase. In addition, an expression vector can include a tag sequence designed to facilitate manipulation or detection (e.g., purification or localization) of the expressed polypeptide. Tag sequences, such as GFP, glutathione S-transferase (GST), polyhistidine, c-myc, hemagglutinin, or FLAG™ tag (Kodak; New Haven, Conn.) sequences typically are expressed as a fusion with the encoded polypeptide. Such tags can be inserted anywhere within the polypeptide including at either the carboxyl or amino terminus.

As used herein, the terms peptide, polypeptide, or protein are used broadly to mean two or more amino acids linked by a peptide bond. Protein, peptide, and polypeptide are also used herein interchangeably to refer to amino acid sequences. It should be recognized that the term polypeptide is not used herein to suggest a particular size or number of amino acids comprising the molecule and that a peptide of the invention can contain up to several amino acid residues or more. As used throughout, subject can be a vertebrate, more specifically a mammal (e.g. a human, horse, cat, dog, cow, pig, sheep, goat, mouse, rabbit, rat, and guinea pig), birds, reptiles, amphibians, fish, and any other animal. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered. As used herein, patient or subject may be used interchangeably and can refer to a subject with a disease or disorder (e.g. cancer). The term patient or subject includes human and veterinary subjects.

A subject at risk of developing a disease or disorder can be genetically predisposed to the disease or disorder, e.g., have a family history or have a mutation in a gene that causes the disease or disorder, or show early signs or symptoms of the disease or disorder. A subject currently with a disease or disorder has one or more than one symptom of the disease or disorder and may have been diagnosed with the disease or disorder.

The methods and agents as described herein are useful for both prophylactic and therapeutic treatment. For prophylactic use, a therapeutically effective amount of the chimeric polypeptides or chimeric nucleic acid sequences encoding the chimeric polypeptides described herein are administered to a subject prior to onset (e.g., before obvious signs of cancer or inflammation) or during early onset (e.g., upon initial signs and symptoms of cancer or inflammation). Prophylactic administration can occur for several days to years prior to the manifestation of symptoms of cancer or inflammation. Prophylactic administration can be used, for example, in the preventative treatment of subjects diagnosed with a genetic predisposition to cancer. Therapeutic treatment involves administering to a subject a therapeutically effective amount of the chimeric polypeptides or nucleic acid sequences encoding the chimeric polypeptides described herein after diagnosis or development of cancer or inflammation (e.g., an autoimmune disease). Prophylactic use may also apply when a patient is undergoing a treatment, e.g., a chemotherapy, in which inflammation is expected.

According to the methods taught herein, the subject is administered an effective amount of the agent (e.g., a chimeric polypeptide). The terms effective amount and effective dosage are used interchangeably. The term effective amount is defined as any amount necessary to produce a desired physiologic response. Effective amounts and schedules for administering the agent may be determined empirically, and making such determinations is within the skill in the art. The dosage ranges for administration are those large enough to produce the desired effect in which one or more symptoms of the disease or disorder are affected (e.g., reduced or delayed). The dosage should not be so large as to cause substantial adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex, type of disease, the extent of the disease or disorder, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosages can vary and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

As used herein the terms treatment, treat, or treating refers to a method of reducing the effects of a disease or condition or symptom of the disease or condition. Thus, in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease or condition or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition.

As used herein, the terms prevent, preventing, and prevention of a disease or disorder refers to an action, for example, administration of the chimeric polypeptide or nucleic acid sequence encoding the chimeric polypeptide, that occurs before or at about the same time a subject begins to show one or more symptoms of the disease or disorder, which inhibits or delays onset or exacerbation of one or more symptoms of the disease or disorder. As used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level. Such terms can include but do not necessarily include complete elimination.

IL-2 variants have been developed that are selective for IL2Rαβγ relative to IL2Rβγ (Shanafelt, A. B., et al., 2000, Nat Biotechnol. 18:1197-202; Cassell, D. J., et. al., 2002, Curr Pharm Des., 8:2171-83). These variants have amino acid substitutions which reduce their affinity for IL2RB. Because IL-2 has undetectable affinity for IL2RG, these variants consequently have reduced affinity for the IL2Rβγ receptor complex and reduced ability to activate IL2Rβγ-expressing cells, but retain the ability to bind IL2RA and the ability to bind and activate the IL2Rαβγ receptor complex.

One of these variants, IL2/N88R (Bay 50-4798), was clinically tested as a low-toxicity version of IL-2 as an immune system stimulator, based on the hypothesis that IL2Rβγ-expressing NK cells are a major contributor to toxicity. Bay 50-4798 was shown to selectively stimulate the proliferation of activated T cells relative to NK cells, and was evaluated in phase I/II clinical trials in cancer patients (Margolin, K., et. al., 2007, Clin Cancer Res., 13:3312-9) and HIV patients (Davey, R. T., et. al., 2008, J Interferon Cytokine Res., 28:89-100). These clinical trials showed that Bay 50-4798 was considerably safer and more tolerable than aldesleukin, and also showed that it increased the levels of CD4+CD25+ T cells, a cell population enriched in Treg cells. Subsequent to these trials, research in the field more fully established the identity of Treg cells and demonstrated that Treg cells selectively express IL2Rαβγ (reviewed in Malek, T. R., et al., 2010, Immunity, 33:153-65).

In addition, mutants can be made that selectively alter the affinity for the CD25 chain relative to native I1-2.

IL-2 can be engineered to produce mutants that bind the IL-2R complex generally or the IL-2Ra subunit specifically with an affinity that differs from that of the corresponding wild-type IL-2 or of a presently available mutant (referred to as C125S, as the cysteine residue at position 125 is replaced with a serine residue).

Accordingly, the present invention features mutant interleukin-2 (IL-2*) polypeptides that include an amino acid sequence that is at least 80% identical to wild-type IL-2 (e.g., 85, 87, 90, 95, 97, 98, or 99% identical) and that bind, as compared to WT IL-2, with higher to the IL-2 trimeric receptor relative to the dimeric IL-2 receptor. Typically, the muteins will also bind an IL-2 receptor α subunit (IL-2Rα) with an affinity that is greater than the affinity with which wild type IL-2 binds the IL-2Rα. The amino acid sequence within mutant IL-2 polypeptides can vary from SEQ ID NO:1 (UniProtKB accession number P60568) by virtue of containing (or only containing) one or more amino acid substitutions, which may be considered conservative or non-conservative substitutions. Non-naturally occurring amino acids can also be incorporated. Alternatively, or in addition, the amino acid sequence can vary from SEQ ID NO:1 (which may be considered the “reference” sequence) by virtue of containing and addition and/or deletion of one or more amino acid residues. More specifically, the amino acid sequence can differ from that of SEQ ID NO:1 by virtue of a mutation at least one of the following positions of SEQ ID NO:1: 1, 4, 8, 9, 10, 11, 13, 15, 26, 29, 30, 31, 35, 37, 46, 48, 49, 54, 61, 64, 67, 68, 69, 71, 73, 74, 75, 76, 79, 88, 89, 90, 92, 99, 101, 103, 114, 125, 128, or 133 (or combinations thereof). As noted, as few as one of these positions may be altered, as may two, three, four, five, six, seven, eight, nine, ten, or 11 or more (including up to all) of the positions. For example, the amino acid sequence can differ from SEQ ID NO:1 at positions 69 and 74 and further at one or more of positions 30, 35, and 128. The amino acid sequence can also differ from SEQ ID NO:2 (as disclosed in U.S. Pat. No. 7,569,215, incorporated herein by reference) at one of the following sets of positions: (a) positions 64, 69, and 74; (b) positions 69, 74, and 101; (c) positions 69, 74, and 128; (d) positions 30, 69, 74, and 103; (e) positions 49, 69, 73, and 76; (f) positions 69, 74, 101, and 133; (g) positions 30, 69, 74, and 128; (h) positions 69, 74, 88, and 99; (i) positions 30, 69, 74, and 128; (j) positions 9, 11, 35, 69, and 74; (k) positions 1, 46, 49, 61, 69, and 79; (l) positions 48, 68, 71, 90, 103, and 114; (m) positions 4, 10, 11, 69, 74, 88, and 133; (n) positions 15, 30 31, 35, 48, 69, 74, and 92; (O) positions 30, 68, 69, 71, 74, 75, 76, and 90; (p) positions 30, 31, 37, 69, 73, 74, 79, and 128; (q) positions 26, 29, 30, 54, 67, 69, 74, and 92; (r) positions 8, 13, 26, 30, 35, 37, 69, 74, and 92; and (s) positions 29, 31, 35, 37, 48, 69, 71, 74, 88, and 89. Aside from mutations at these positions, the amino acid sequence of the mutant IL-2 polypeptide can otherwise be identical to SEQ ID NO:1. With respect to specific substitutions, the amino acid sequence can differ from SEQ ID NO:1 by virtue of having one or more of the following mutations: A1T, S4P, K8R, K9T, T10A, Q11R, Q13R, E15K, N26D, N29S, N30S, N30D, N30T, Y31H, Y31C, K35R, T37A, T37R, M46L, K48E, K49R, K49E, K54R, E61D, K64R, E67G, E68D, V69A, N71T, N71A, N71R, A73V, Q74P, S75P, K76E, K76R, H79R, N88D, I89V, N90H, I92T, S99P, T101A, F103S, I114V, I128T, I128A, T133A, or T133N. Our nomenclature is consistent with that of the scientific literature, where the single letter code of the amino acid in the wild-type or reference sequence is followed by its position within the sequence and then by the single letter code of the amino acid with which it is replaced. Thus, A1T designates a substitution of the alanine residue a position 1 with threonine. Other mutant polypeptides within the scope of the invention include those that include a mutant of SEQ ID NO:2 having substitutions at V69 (e.g. A) and Q74 (e.g., P). For example, the amino acid sequence can include one of the following sets of mutations with respect to SEQ ID NO:2: (a) K64R, V69A, and Q74P; (b) V69A, Q74P, and T101A; (c) V69A, Q74P, and I128T; (d) N30D, V69A, Q74P, and F103S; (e) K49E, V69A, A73V, and K76E; (f) V69A, Q74P, T101A, and T133N; (g) N30S, V69A, Q74P, and I128A; (h) V69A, Q74P, N88D, and S99P; (i) N30S, V69A, Q74P, and I128T; (j) K9T, Q11R, K35R, V69A, and Q74P; (k) A1T, M46L, K49R, E61D, V69A, and H79R; (1) K48E, E68D, N71T, N90H, F103S, and I114V; (m) S4P, T10A, Q11R, V69A, Q74P, N88D, and T133A; (n) E15K, N30S Y31H, K35R, K48E, V69A, Q74P, and I92T; (o) N30S, E68D, V69A, N71A, Q74P, S75P, K76R, and N90H; (p) N30S, Y31C, T37A, V69A, A73V, Q74P, H79R, and I128T; (q) N26D, N29S, N30S, K54R, E67G, V69A, Q74P, and I92T; (r) K8R, Q13R, N26D, N30T, K35R, T37R, V69A, Q74P, and I92T; and (s) N29S, Y31H, K35R, T37A, K48E, V69A, N71R, Q74P, N88D, and I89V. SEQ ID NO:2 is disclosed in U.S. Pat. No. 7,569,215, which is incorporated herein by reference as an exemplary IL-2 polypeptide sequence that can be used in the invention.

As noted above, any of the mutant IL-2 polypeptides disclosed herein can include the sequences described; they can also be limited to the sequences described and otherwise identical to SEQ ID NO:1. Moreover, any of the mutant IL-2 polypeptides described herein can optionally include a substitution of the cysteine residue at position 125 with another residue (e.g., serine) and/or can optionally include a deletion of the alanine residue at position 1 of SEQ ID NO:1.

The mutant IL-2 polypeptides disclosed herein can bind to the IL-2Rα subunit with a K_(d) of less than about 28 nM (e.g., less than about 25 nM; less than about 5 nM; about 1 nM; less than about 500 pM; or less than about 100 pM). More specifically, a mutant IL-2 polypeptide can have an affinity equilibrium constant less than 1.0 nM (e.g., about 0.8, 0.6, 0.4, or 0.2 nM). Affinity can also be expressed as a relative rate of dissociation from an IL-2Rα subunit or from an IL-2 receptor complex (e.g., a complex expressed on the surface of a cell or otherwise membrane bound). For example, the mutant IL-2 polypeptides can dissociate from, e.g., IL-2Rα, at a decreased rate relative to a wild-type polypeptide or to an IL-2 based therapeutic, e.g., IL-2*. Alternatively, affinity can be characterized as the time, or average time, an IL-2* polypeptide persists on, for example, the surface of a cell expressing an IL-2R. For example, an IL-2*polypeptide can persist on the receptor for at least about 2, 5, 10, 50, 100, or 250 times (or more).

Disclosed are materials, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

Publications cited herein and the material for which they are cited are hereby specifically incorporated by reference in their entireties.

EXAMPLES

The following are examples of methods and compositions of the invention. It is understood that various other embodiments may be practiced, given the general description provided herein.

Example 1: Detection of IL-2, IL-2 Mutein, IL-2Rα and IL-2R₇ in Fusion Proteins by ELISA

IL-2 mutein is detected with a commercially available antibody, e.g., the anti-IL-2 monoclonal (JES6-1A12) (BD Pharmingen; San Jose, Calif.). A positive control is used to show whether the monoclonal antibody recognizes the cytokine or mutein. Antibodies against IL-2Rα and IL-2Rγ chain are also used. Wells of a 96-well plate are coated with an antibody (2.5 μg/ml) in PBS. Wells are blocked with 5% non-fat milk in PBS with 0.2% Tween®20 (PBS-M-Tw) and fusion proteins are added for 1-2 hours at 37° C. After washing, an anti-IL-2 biotin-labeled antibody, e.g., JES5H4 (BD Pharmingen) is added and binding is detected using Strepavidin HRP (Southern Biotechnology Associates; Birmingham, Ala.). The ELISA plate is developed by adding 50 μl O-phenylenediamine (OPD) (Sigma-Aldrich) in 0.1M Citrate pH 4.5 and 0.04% H₂O₂, stopped by adding 50 μl/well 2N H₂SO₄ and the absorbance was read at 490 nm.

Example 2: Protease Cleavage of Fusion Protein by MMP9 Protease

One of skill in the art would be familiar with methods of setting up protein cleavage assay. 100 ug of protein in 1×PBS pH 7.4 were cleaved with 1 μg active MMP9 (Sigma catalog #SAE0078-50 or Enzo catalog BML-SE360) and incubated at room temperature for up to 16 hours. Digested protein is subsequently used in functional assays or stored at −80° C. prior to testing. Extent of cleavage was monitored by SDS PAGE using methods well known in the art. As shown in FIGS. 10, 13, 18A, 18B, 24B, 24C, and 27A full cleavage of the fusion proteins by MMP9 protease is seen.

Example 3: CTLL-2 Assay

CTLL2 cells (ATCC) were plated in suspension at a concentration of 500,000 cells/well in culture media with or without 40 mg/ml human serum albumin (HSA) and stimulated with a dilution series of recombinant hIL2 or activatable hIL2 for 72 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved activatable hIL2 was tested. Cleaved activatable hIL2 was generated by incubation with active MMP9. Cell activity was assessed using a CellTiter-Glo (Promega) luminescence-based cell viability assay.

Example 4: Protease Cleavage of the IL-2/IL-2Rα/IL-2Rγ Chimeric Polypeptide Results in Increased Accessibility to Antibodies and Biologically Active IL-2 Mutein

The IL-2 mutein fusion proteins are biochemically characterized before and after cleavage with a protease, e.g., PSA. Immunoblot analyses will show that the fusion proteins can be cleaved by PSA and that there is an increase in intensity of the predicted low molecular weight cleavage product of approximately 20 kDa reactive with an anti-IL-2 antibody after treatment of the samples with PSA. The degree of cleavage is dependent upon the amount of PSA as well as the time of incubation. Interestingly, when the fusion protein is analyzed before and after PSA treatment by ELISA, it was found that the apparent amount of IL-2 is increased after PSA cleavage. In this experiment, there is an approximately 2 or 4-fold increase in the apparent amount of IL-2 detected using this sandwich ELISA depending on the construct, suggesting that the antibody binding is partially hindered in the intact fusion protein. Aliquots of the same samples are also analyzed after PSA treatment using the CTLL-2 cell line that requires IL-2 for growth and survival and the viability of cells can be ascertained using the colorimetric MTT assay. In this assay, the more a supernatant can be diluted, the more biologically active IL-2 it contains, and there is an increase in the amount of biologically active IL-2 after PSA cleavage. The amount of IL-2 mutein increase will suggest that after PSA cleavage there is an increase in the predicted low molecular weight cleavage fragment of approximately 20 kDa reactive with an anti-IL-2 antibody, an increase in antibody accessibility, and most importantly, an increase in the amount of biologically active IL-2 mutein.

Example 5. In Vivo Delivery of a Protease Activated Fusion Protein Results in Decreased Tumor Growth

The chimeric polypeptide is examined to determine if it could have biological effects in vivo. For these experiments a system is used in which tumor cells injected intraperitoneally rapidly and preferentially attach and grow initially on the milky spots, a series of organized immune aggregates found on the omentum (Gerber et al., Am. J. Pathol. 169:1739-52 (2006)). This system offers a convenient way to examine the effects of fusion protein treatment on tumor growth since fusion proteins can be delivered intraperitoneally multiple times and tumor growth can be analyzed by examining the dissociated omental cells. For these experiments, the Colon 38 cell line, a rapidly growing tumor cell line that expresses both MMP2 and MMP9 in vitro, may be used. The omental tissue normally expresses a relatively small amount of MMP2 and MMP9, but, when Colon 38 tumor is present on the omentum, MMP levels increase. Using this tumor model, the ability of IL-2 mutein fusion proteins to affect tumor growth is examined. Colon 38 cells are injected intraperitoneally, allowed to attach and grow for 1 day, and then treated daily with fusion protein interaperitoneally. At day 7, the animals are sacrificed and the omenta examined for tumor growth using flow cytometry and by a colony-forming assay.

Example 6: Construction of an Exemplary Activatable IL2 Protein Targeting CD20 Generation of an Activatable IL2 Domain

An IL-2 polypeptide capable of binding to CD20 polypeptide present in a tumor or on a tumor cell is produced as follows. A nucleic acid is produced that contains nucleic acid sequences: (1) encoding an IFNγ polypeptide sequence and (2) one or more polypeptide linkers. Activatable interleukin plasmid constructs can have optional Flag, His or other affinity tags, and are electroporated into HEK293 or other suitable human or mammalian cell lines and purified. Validation assays include T cell activation assays using T cells responsive to IFNγ stimulation in the presence of a protease.

Generation of a scFv CD20 Binding Domain

CD20 is one of the cell surface proteins present on B-lymphocytes. CD20 antigen is found in normal and malignant pre-B and mature B lymphocytes, including those in over 90% of B-cell non-Hodgkin's lymphomas (NHL). The antigen is absent in hematopoietic stem cells, activated B lymphocytes (plasma cells) and normal tissue. As such, several antibodies mostly of murine origin have been described: 1FS, 2B8/C2B8, 2H7, and 1H4.

Human or humanized anti-CD20 antibodies are therefore used to generate scFv sequences for CD20 binding domains of an activatable interleukin protein. DNA sequences coding for human or humanized VL and VH domains are obtained, and the codons for the constructs are, optionally, optimized for expression in cells from Homo sapiens. The order in which the VL and VH domains appear in the scFv is varied (i.e., VL-VH, or VH-VL orientation), and three copies of the “G4S” (SEQ ID NO.: 449) or “G4S” (SEQ ID NO.: 449) subunit (G₄S)₃ (SEQ ID NO.: 452) connect the variable domains to create the scFv domain. Anti-CD20 scFv plasmid constructs can have optional Flag, His or other affinity tags, and are electroporated into HEK293 or other suitable human or mammalian cell lines and purified. Validation assays include binding analysis by FACS, kinetic analysis using Proteon, and staining of CD20-expressing cells.

Cloning of DNA Expression Constructs Encoding the Activatable IL2 Protein

The activatable IL2 construct with protease cleavage site domains are used to construct an activatable interleukin protein in combination with an anti-CD20 scFv domain and a serum half-life extension element (e.g., a HSA binding peptide or VH domain). For expression of an activatable interleukin protein in CHO cells, coding sequences of all protein domains are cloned into a mammalian expression vector system. In brief, gene sequences encoding the activatable interleukin domain, serum half-life extension element, and CD20 binding domain along with peptide linkers L1 and L2 are separately synthesized and subcloned. The resulting constructs are then ligated together in the order of CD20 binding domain—L1-IL2 subunit 1-L2-protease cleavage domain—L3-IL2 subunit 2-L4-anti-CD20 scFv-L5-serum half-life extension element to yield a final construct. All expression constructs are designed to contain coding sequences for an N-terminal signal peptide and a C-terminal hexahistidine (6×His)-tag (SEQ ID NO. 354) to facilitate protein secretion and purification, respectively.

Expression of Activatable IL2 Proteins in Stably Transfected CHO Cells

A CHO cell expression system (Flp-In®, Life Technologies), a derivative of CHO-K1 Chinese Hamster ovary cells (ATCC, CCL-61) (Kao and Puck, Proc. Natl. Acad Sci USA 1968; 60(4):1275-81), is used. Adherent cells are subcultured according to standard cell culture protocols provided by Life Technologies.

For adaption to growth in suspension, cells are detached from tissue culture flasks and placed in serum-free medium. Suspension-adapted cells are cryopreserved in medium with 10% DMSO.

Recombinant CHO cell lines stably expressing secreted activatable interleukin proteins are generated by transfection of suspension-adapted cells. During selection with the antibiotic Hygromycin B viable cell densities are measured twice a week, and cells are centrifuged and resuspended in fresh selection medium at a maximal density of 0.1×10⁶ viable cells/mL. Cell pools stably expressing activatable interleukin proteins are recovered after 2-3 weeks of selection at which point cells are transferred to standard culture medium in shake flasks. Expression of recombinant secreted proteins is confirmed by performing protein gel electrophoresis or flow cytometry. Stable cell pools are cryopreserved in DMSO containing medium.

Activatable IL2 proteins are produced in 10-day fed-batch cultures of stably transfected CHO cell lines by secretion into the cell culture supernatant. Cell culture supernatants are harvested after 10 days at culture viabilities of typically >75%. Samples are collected from the production cultures every other day and cell density and viability are assessed. On day of harvest, cell culture supernatants are cleared by centrifugation and vacuum filtration before further use.

Protein expression titers and product integrity in cell culture supernatants are analyzed by SDS-PAGE.

Purification of Activatable IL2 Proteins

Activatable IL2 proteins are purified from CHO cell culture supernatants in a two-step procedure. The constructs are subjected to affinity chromatography in a first step followed by preparative size exclusion chromatography (SEC) on Superdex 200 in a second step. Samples are buffer-exchanged and concentrated by ultrafiltration to a typical concentration of >1 mg/mL. Purity and homogeneity (typically >90%) of final samples are assessed by SDS PAGE under reducing and non-reducing conditions, followed by immunoblotting using an anti-HSA or anti idiotype antibody as well as by analytical SEC, respectively. Purified proteins are stored at aliquots at −80° C. until use.

Example 7: Determination of Antigen Affinity by Flow Cytometry

The activatable interleukin proteins of Example 6 are tested for their binding affinities to human CD20⁺ cells and cynomolgus CD20⁺ cells.

CD20⁺ cells are incubated with 100 μL of serial dilutions of the activatable interleukin proteins of Example 1 and at least one protease. After washing three times with FACS buffer the cells are incubated with 0.1 mL of 10 μg/mL mouse monoclonal anti-idiotype antibody in the same buffer for 45 min on ice. After a second washing cycle, the cells are incubated with 0.1 mL of 15 μg/mL FITC-conjugated goat anti-mouse IgG antibodies under the same conditions as before. As a control, cells are incubated with the anti-His IgG followed by the FITC-conjugated goat anti-mouse IgG antibodies without the activatable IL2 proteins. The cells were then washed again and resuspended in 0.2 mL of FACS buffer containing 2 μg/mL propidium iodide (PI) in order to exclude dead cells. The fluorescence of 1×10⁴ living cells is measured using a Beckman-Coulter FC500 MPL flow cytometer using the MXP software (Beckman-Coulter, Krefeld, Germany) or a Millipore Guava EasyCyte flow cytometer using the Incyte software (Merck Millipore, Schwalbach, Germany). Mean fluorescence intensities of the cell samples are calculated using CXP software (Beckman-Coulter, Krefeld, Germany) or Incyte software (Merck Millipore, Schwalbach, Germany). After subtracting the fluorescence intensity values of the cells stained with the secondary and tertiary reagents alone the values are then used for calculation of the K_(D) values with the equation for one-site binding (hyperbola) of the GraphPad Prism (version 6.00 for Windows, GraphPad Software, La Jolla Calif. USA).

CD20 binding and crossreactivity are assessed on the human CD20+ tumor cell lines. The K_(D) ratio of crossreactivity is calculated using the K_(D) values determined on the CHO cell lines expressing either recombinant human or recombinant cynomolgus antigens.

Example 8: Cytotoxicity Assay

The activatable interleukin protein of Example 6 is evaluated in vitro on its mediation of immune response to CD20+ target cells.

Fluorescence labeled CD20+ REC-1 cells (a Mantle cell lymphoma cell line, ATCC CRL-3004) are incubated with isolated PBMC of random donors or CB15 T-cells (standardized T-cell line) as effector cells in the presence of the activatable IL2 protein of Example 5 and at least one protease. After incubation for 4 h at 37° C. in a humidified incubator, the release of the fluorescent dye from the target cells into the supernatant is determined in a spectrofluorimeter. Target cells incubated without the activatable IL2 protein of Example land target cells totally lysed by the addition of saponin at the end of the incubation serve as negative and positive controls, respectively.

Based on the measured remaining living target cells, the percentage of specific cell lysis is calculated according to the following formula: [1−(number of living targets_((sample))/number of living targets_((spontaneous)))]×100%. Sigmoidal dose response curves and EC₅₀ values are calculated by non-linear regression/4-parameter logistic fit using the GraphPad Software. The lysis values obtained for a given antibody concentration are used to calculate sigmoidal dose-response curves by 4 parameter logistic fit analysis using the Prism software.

Example 9: Pharmacokinetics of Activatable Interleukin Proteins

The activatable interleukin protein of Example 6 is evaluated for half-time elimination in animal studies.

The activatable IL2 protein is administered to cynomolgus monkeys as a 0.5 mg/kg bolus injection into the saphenous vein. Another cynomolgus monkey group receives a comparable IL2 construct in size, but lacking a serum half-life extension element. A third and fourth group receive an IL2 construct with serum half-life extension element and a cytokine with CD20 and serum half-life extension elements respectively, and both comparable in size to the activatable interleukin protein. Each test group consists of 5 monkeys. Serum samples are taken at indicated time points, serially diluted, and the concentration of the proteins is determined using a binding ELISA to CD20.

Pharmacokinetic analysis is performed using the test article plasma concentrations. Group mean plasma data for each test article conforms to a multi-exponential profile when plotted against the time post-dosing. The data are fit by a standard two-compartment model with bolus input and first-order rate constants for distribution and elimination phases. The general equation for the best fit of the data for i.v. administration is: c(t)=Ae^(−αt)+Be^(−βt), where c(t) is the plasma concentration at time t, A and B are intercepts on the Y-axis, and α and β are the apparent first-order rate constants for the distribution and elimination phases, respectively. The α-phase is the initial phase of the clearance and reflects distribution of the protein into all extracellular fluid of the animal, whereas the second or β-phase portion of the decay curve represents true plasma clearance. Methods for fitting such equations are well known in the art. For example, A=DN(α−k21)/(α−β), B=DN(β−k21)/(α−β), and α and β (for α>β) are roots of the quadratic equation: r²+(k12+k21+k10)r+k21k10=0 using estimated parameters of V=volume of distribution, k10=elimination rate, k12=transfer rate from compartment 1 to compartment 2 and k21=transfer rate from compartment 2 to compartment 1, and D=the administered dose.

Data analysis: Graphs of concentration versus time profiles are made using KaleidaGraph (KaleidaGraph™ V. 3.09 Copyright 1986-1997. Synergy Software. Reading, Pa.). Values reported as less than reportable (LTR) are not included in the PK analysis and are not represented graphically. Pharmacokinetic parameters are determined by compartmental analysis using WinNonlin software (WinNonlin® Professional V. 3.1 WinNonlin™ Copyright 1998-1999. Pharsight Corporation. Mountain View, Calif.). Pharmacokinetic parameters are computed as described in Ritschel W A and Kearns G L, 1999, IN: Handbook Of Basic Pharmacokinetics Including Clinical Applications, 5th edition, American Pharmaceutical Assoc., Washington, D.C.

It is expected that the activatable interleukin protein of Example 5 has improved pharmacokinetic parameters such as an increase in elimination half-time as compared to proteins lacking a serum half-life extension element.

Example 10: Xenograft Tumor Model

The activatable IL2 protein of Example 6 is evaluated in a xenograft model.

Female immune-deficient NOD/scid mice are sub-lethally irradiated (2 Gy) and subcutaneously inoculated with 4×10⁶ Ramos RA1 cells into the right dorsal flank. When tumors reach 100 to 200 mm³, animals are allocated into 3 treatment groups. Groups 2 and 3 (8 animals each) are intraperitoneally injected with 1.5×10⁷ activated human T-cells. Three days later, animals from Group 3 are subsequently treated with a total of 9 intravenous doses of 50 sg activatable interleukin protein of Example 1 (qd×9d). Groups 1 and 2 are only treated with vehicle. Body weight and tumor volume are determined for 30 days.

It is expected that animals treated with the activatable interleukin protein of Example 5 have a statistically significant delay in tumor growth in comparison to the respective vehicle-treated control group.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Example 11: Mouse IFNγ WEHI Cell Survival Assay

WEHI279 cells (ATCC) were plated in suspension at a concentration of 25,000 cells/well in culture media with or without 1.5% human serum albumin (HSA) and stimulated with a dilution series of recombinant mIFNγ or inducible mIFNγ for 72 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved inducible mIFNγ was tested. Cleaved inducible mIFNg was generated by incubation with active MMP9. Cell survival was assessed using a CellTiter-Glo (Promega) luminescence-based cell viability assay. The EC50 values for cleaved inducible mIFNg molecules were at least 100× more potent than un-cleaved inducible mIFNg molecules. As shown in FIGS. 16A-16F, greater inducibility was seen in assays wherein the culture media contained human serum albumin.

Example 12: Mouse IFNγ B16 Reporter and Mouse IFNα/β B16 Reporter Cell Assays

B16-Blue IFNγ cells (InvivoGen) were plated at a concentration of 75,000 cells/well in culture media with or without 1.5% human serum albumin (HSA) and stimulated with a dilution series of recombinant mIFNγ or inducible mIFNγ for 24 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved inducible mIFNγ was tested. Cleaved inducible mIFNγ was generated by incubation with active MMP9. Supernatants were harvested, and SEAP activation was assessed by adding QUANTI-Blue Reagent (InvivoGen), incubating at 37° C. for 2 hours, and measuring absorbance at 620 nm. Results are shown in FIGS. 17A-17F, 19A, 19B, 22A, 22B, 23A, 23B, and 28A-28N. This experiment was repeated with for IFNα fusion proteins using B16-Blue IFNα/β cells. The EC50 values for cleaved inducible mIFNα molecules were at least 100× more potent than un-cleaved inducible mIFNα molecules.

B16-Blue IFN-α/p cells (InvivoGen) were plated in suspension at a density of 75,000 cells/well in culture media with or without 15 mg/ml mouse serum albumin (HSA) and stimulated with a dilution series of recombinant mouse IFNα (or IFNβ) and activatable mouse IFNα (or IFNβ) for 20-24 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved activatable IFNα (or IFNβ) was tested. Cleaved inducible IFNα (or IFNβ) was generated by incubation with active recombinant protease. Stimulation of B16-Blue IFN-α/β cells with IFNα (or IFNβ) induces expression of Secreted Alkaline Phosphatase (SEAP) from an ISRE-ISG54-SEAP reporter. IFNα (or IFNβ) activity was assessed by quantification of SEAP activity using the reagent QUANTI-Blue (InvivoGen), a colorimetric based assay. Results are shown in FIGS. 10A-10J.

Example 13. In Vivo Delivery of a Protease Activated Fusion Protein Results in Decreased Tumor Growth

The chimeric polypeptide is examined to determine if it could have biological effects in vivo. For these experiments a system is used in which tumor cells injected intraperitoneally rapidly and preferentially attach and grow initially on the milky spots, a series of organized immune aggregates found on the omentum (Gerber et al., Am. J. Pathol. 169:1739-52 (2006)). This system offers a convenient way to examine the effects of fusion protein treatment on tumor growth since fusion proteins can be delivered intraperitoneally multiple times and tumor growth can be analyzed by examining the dissociated omental cells. For these experiments, the Colon 38 cell line, a rapidly growing tumor cell line that expresses both MMP2 and MMP9 in vitro, may be used. The omental tissue normally expresses a relatively small amount of MMP2 and MMP9, but, when Colon 38 tumor is present on the omentum, MMP levels increase. Using this tumor model, the ability of IFN fusion proteins to affect tumor growth is examined. Colon 38 cells are injected intraperitoneally, allowed to attach and grow for 1 day, and then treated daily with fusion protein interaperitoneally. At day 7, the animals are sacrificed and the omenta examined for tumor growth using flow cytometry and by a colony-forming assay.

Example 13b: The Chimeric Polypeptide was Examined to Determine its Biological Effects In Vivo

The MC38 cell line, a rapidly growing colon adenocarcinoma cell line that expresses MMP9 in vitro, was used. Using this tumor model, the ability of IFNγ fusion proteins to affect tumor growth was examined. MC38 cells were injected subcutaneously, allowed to grow for 10-14 days, and then treated with fusion protein twice weekly intraperitoneally for a total of four doses, at the levels shown in FIG. 21A-21C. As a comparator, wild-type mIFNγ was administered at the dose levels indicated, twice daily for 2 weeks on a 5 day on/2 day off schedule (10 total doses). Tumor growth and body weight were monitored approximately twice per week for two weeks.

Example 14: Construction of an Exemplary IFNγ Protein Targeting CD20 Generation of an Activatable Cytokine Domain

An IFNγ polypeptide capable of binding to CD20 polypeptide present in a tumor or on a tumor cell is produced as follows. A nucleic acid is produced that contains nucleic acid sequences: (1) encoding an IFNγ polypeptide sequence and (2) one or more polypeptide linkers. Activatable IFNγ plasmid constructs can have optional Flag, His or other affinity tags, and are electroporated into HEK293 or other suitable human or mammalian cell lines and purified. Validation assays include T cell activation assays using T cells responsive to IFNγ stimulation in the presence of a protease.

Generation of a scFv CD20 Binding Domain

CD20 is one of the cell surface proteins present on B-lymphocytes. CD20 antigen is found in normal and malignant pre-B and mature B lymphocytes, including those in over 90% of B-cell non-Hodgkin's lymphomas (NHL). The antigen is absent in hematopoietic stem cells, activated B lymphocytes (plasma cells) and normal tissue. As such, several antibodies mostly of murine origin have been described: 1F5, 2B8/C2B8, 2H7, and 1H4.

Human or humanized anti-CD20 antibodies are therefore used to generate scFv sequences for CD20 binding domains of an activatable IFNγ protein. DNA sequences coding for human or humanized VL and VH domains are obtained, and the codons for the constructs are, optionally, optimized for expression in cells from Homo sapiens. The order in which the VL and VH domains appear in the scFv is varied (i.e., VL-VH, or VH-VL orientation), and three copies of the “G4S” (SEQ ID NO.: 449) or “G₄S” (SEQ ID NO.: 449) subunit (G₄S)₃ (SEQ ID NO.: 452) connect the variable domains to create the scFv domain. Anti-CD20 scFv plasmid constructs can have optional Flag, His or other affinity tags, and are electroporated into HEK293 or other suitable human or mammalian cell lines and purified. Validation assays include binding analysis by FACS, kinetic analysis using Proteon, and staining of CD20-expressing cells.

Cloning of DNA Expression Constructs Encoding the Activatable IFNγ Protein

The activatable IFNγ construct with protease cleavage site domains are used to construct an activatable IFNγ protein in combination with an anti-CD20 scFv domain and a serum half-life extension element (e.g., a HSA binding peptide or VH domain), with the domains organized. For expression of an activatable IFNγ protein in CHO cells, coding sequences of all protein domains are cloned into a mammalian expression vector system. In brief, gene sequences encoding the activatable IFNγ domain, serum half-life extension element, and CD20 binding domain along with peptide linkers L1 and L2 are separately synthesized and subcloned. The resulting constructs are then ligated together in the order of CD20 binding domain—L1-IFNγ subunit 1-L2-protease cleavage domain—L3-IFNγ subunit2-L4-anti-CD20 scFv-L5-serum half-life extension element to yield a final construct. All expression constructs are designed to contain coding sequences for an N-terminal signal peptide and a C-terminal hexahistidine (6×His)-tag (SEQ ID NO.: 354) to facilitate protein secretion and purification, respectively.

Expression of Activatable IFNγ Proteins in Stably Transfected CHO Cells

A CHO cell expression system (Flp-In®, Life Technologies), a derivative of CHO-K1 Chinese Hamster ovary cells (ATCC, CCL-61) (Kao and Puck, Proc. Natl. Acad Sci USA 1968; 60(4):1275-81), is used. Adherent cells are subcultured according to standard cell culture protocols provided by Life Technologies.

For adaption to growth in suspension, cells are detached from tissue culture flasks and placed in serum-free medium. Suspension-adapted cells are cryopreserved in medium with 10% DMSO.

Recombinant CHO cell lines stably expressing secreted activatable IFNγ proteins are generated by transfection of suspension-adapted cells. During selection with the antibiotic Hygromycin B viable cell densities are measured twice a week, and cells are centrifuged and resuspended in fresh selection medium at a maximal density of 0.1×10⁶ viable cells/mL. Cell pools stably expressing activatable IFNγ proteins are recovered after 2-3 weeks of selection at which point cells are transferred to standard culture medium in shake flasks. Expression of recombinant secreted proteins is confirmed by performing protein gel electrophoresis or flow cytometry. Stable cell pools are cryopreserved in DMSO containing medium.

Activatable IFNγ proteins are produced in 10-day fed-batch cultures of stably transfected CHO cell lines by secretion into the cell culture supernatant. Cell culture supernatants are harvested after 10 days at culture viabilities of typically >75%. Samples are collected from the production cultures every other day and cell density and viability are assessed. On day of harvest, cell culture supernatants are cleared by centrifugation and vacuum filtration before further use.

Protein expression titers and product integrity in cell culture supernatants are analyzed by SDS-PAGE.

Purification of Activatable IFNγ Proteins

Activatable IFNγ proteins are purified from CHO cell culture supernatants in a two-step procedure. The constructs are subjected to affinity chromatography in a first step followed by preparative size exclusion chromatography (SEC) on Superdex 200 in a second step. Samples are buffer-exchanged and concentrated by ultrafiltration to a typical concentration of >1 mg/mL. Purity and homogeneity (typically >90%) of final samples are assessed by SDS PAGE under reducing and non-reducing conditions, followed by immunoblotting using an anti-HSA or anti idiotype antibody as well as by analytical SEC, respectively. Purified proteins are stored at aliquots at −80° C. until use.

Example 15: Determination of Antigen Affinity by Flow Cytometry

The activatable IFNγ proteins of Example 1 are tested for their binding affinities to human CD20⁺ cells and cynomolgus CD20⁺ cells.

CD20⁺ cells are incubated with 100 μL of serial dilutions of the activatable IFNγ proteins of Example 1 and at least one protease. After washing three times with FACS buffer the cells are incubated with 0.1 mL of 10 μg/mL mouse monoclonal anti-idiotype antibody in the same buffer for 45 min on ice. After a second washing cycle, the cells are incubated with 0.1 mL of 15 μg/mL FITC-conjugated goat anti-mouse IgG antibodies under the same conditions as before. As a control, cells are incubated with the anti-His IgG followed by the FITC-conjugated goat anti-mouse IgG antibodies without the activatable IFNγ proteins. The cells were then washed again and resuspended in 0.2 mL of FACS buffer containing 2 μg/mL propidium iodide (PI) in order to exclude dead cells. The fluorescence of 1×10⁴ living cells is measured using a Beckman-Coulter FC500 MPL flow cytometer using the MXP software (Beckman-Coulter, Krefeld, Germany) or a Millipore Guava EasyCyte flow cytometer using the Incyte software (Merck Millipore, Schwalbach, Germany). Mean fluorescence intensities of the cell samples are calculated using CXP software (Beckman-Coulter, Krefeld, Germany) or Incyte software (Merck Millipore, Schwalbach, Germany). After subtracting the fluorescence intensity values of the cells stained with the secondary and tertiary reagents alone the values are then used for calculation of the K_(D) values with the equation for one-site binding (hyperbola) of the GraphPad Prism (version 6.00 for Windows, GraphPad Software, La Jolla Calif. USA).

CD20 binding and crossreactivity are assessed on the human CD20⁺ tumor cell lines. The K_(D) ratio of crossreactivity is calculated using the K_(D) values determined on the CHO cell lines expressing either recombinant human or recombinant cynomolgus antigens.

Example 16: Cytotoxicity Assay

The activatable IFNγ protein of Example 5 is evaluated in vitro on its mediation of immune response to CD20⁺ target cells.

Fluorescence labeled CD20⁺ REC-1 cells (a Mantle cell lymphoma cell line, ATCC CRL-3004) are incubated with isolated PBMC of random donors or CB15 T-cells (standardized T-cell line) as effector cells in the presence of the activatable IFNγ protein of Example 5 and at least one protease. After incubation for 4 h at 37° C. in a humidified incubator, the release of the fluorescent dye from the target cells into the supernatant is determined in a spectrofluorimeter. Target cells incubated without the activatable IFNγ protein of Example 5 and target cells totally lysed by the addition of saponin at the end of the incubation serve as negative and positive controls, respectively.

Based on the measured remaining living target cells, the percentage of specific cell lysis is calculated according to the following formula: [1−(number of living targets_((sample))/number of living targets_((spontaneous)))]×100%. Sigmoidal dose response curves and EC₅₀ values are calculated by non-linear regression/4-parameter logistic fit using the GraphPad Software. The lysis values obtained for a given antibody concentration are used to calculate sigmoidal dose-response curves by 4 parameter logistic fit analysis using the Prism software.

Example 17: Pharmacokinetics of Activatable IFNγ Proteins

The activatable IFNγ protein of Example 5 is evaluated for half-time elimination in animal studies.

The activatable IFNγ protein is administered to cynomolgus monkeys as a 0.5 mg/kg bolus injection into the saphenous vein. Another cynomolgus monkey group receives a comparable cytokine in size, but lacking a serum half-life extension element. A third and fourth group receive a cytokine with serum half-life extension elements and a cytokine with CD20 and serum half-life extension elements respectively, and both comparable in size to the activatable IFNγ protein. Each test group consists of 5 monkeys. Serum samples are taken at indicated time points, serially diluted, and the concentration of the proteins is determined using a binding ELISA to CD20.

Pharmacokinetic analysis is performed using the test article plasma concentrations. Group mean plasma data for each test article conforms to a multi-exponential profile when plotted against the time post-dosing. The data are fit by a standard two-compartment model with bolus input and first-order rate constants for distribution and elimination phases. The general equation for the best fit of the data for i.v. administration is: c(t)=Ae^(−αt)+Be^(−βt), where c(t) is the plasma concentration at time t, A and B are intercepts on the Y-axis, and α and β are the apparent first-order rate constants for the distribution and elimination phases, respectively. The α-phase is the initial phase of the clearance and reflects distribution of the protein into all extracellular fluid of the animal, whereas the second or β-phase portion of the decay curve represents true plasma clearance. Methods for fitting such equations are well known in the art. For example, A=DN(α−k21)/(α−β), B=DN(β−k21)/(α−β), and α and β (for α>β) are roots of the quadratic equation: r2+(k12+k21+k10)r+k21k10=0 using estimated parameters of V=volume of distribution, k10=elimination rate, k12=transfer rate from compartment 1 to compartment 2 and k21=transfer rate from compartment 2 to compartment 1, and D=the administered dose.

Data analysis: Graphs of concentration versus time profiles are made using KaleidaGraph (KaleidaGraph™ V. 3.09 Copyright 1986-1997. Synergy Software. Reading, Pa.). Values reported as less than reportable (LTR) are not included in the PK analysis and are not represented graphically. Pharmacokinetic parameters are determined by compartmental analysis using WinNonlin software (WinNonlin® Professional V. 3.1 WinNonlin™ Copyright 1998-1999. Pharsight Corporation. Mountain View, Calif.). Pharmacokinetic parameters are computed as described in Ritschel W A and Kearns G L, 1999, IN: Handbook Of Basic Pharmacokinetics Including Clinical Applications, 5th edition, American Pharmaceutical Assoc., Washington, D.C.

It is expected that the activatable IFNγ protein of Example 5 has improved pharmacokinetic parameters such as an increase in elimination half-time as compared to proteins lacking a serum half-life extension element.

Example 18: Xenograft Tumor Model

The activatable IFNγ protein of Example 5 is evaluated in a xenograft model.

Female immune-deficient NOD/scid mice are sub-lethally irradiated (2 Gy) and subcutaneously inoculated with 4×10⁶ Ramos RA1 cells into the right dorsal flank. When tumors reach 100 to 200 mm³, animals are allocated into 3 treatment groups. Groups 2 and 3 (8 animals each) are intraperitoneally injected with 1.5×10⁷ activated human T-cells. Three days later, animals from Group 3 are subsequently treated with a total of 9 intravenous doses of 50 sg activatable IFNγ protein of Example 5 (qd×9d). Groups 1 and 2 are only treated with vehicle. Body weight and tumor volume are determined for 30 days.

It is expected that animals treated with the activatable IFNγ protein of Example 5 have a statistically significant delay in tumor growth in comparison to the respective vehicle-treated control group.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Example 19: HEK-Blue Assay

HEK-Blue IL12 cells (InvivoGen) were plated in suspension at a concentration of 50,000 cells/well in culture media with or without 15 or 40 mg/ml human serum albumin (HSA) and stimulated with a dilution series of recombinant hIL12, chimeric IL12 (mouse p35/human p40) or activatable hIL12 for 20-24 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved activatable hIL12 was tested. Cleaved inducible hIL12 was generated by incubation with active MMP9. IL12 activity was assessed by quantification of Secreted Alkaline Phosphatase (SEAP) activity using the reagent QUANTI-Blue (InvivoGen), a colorimetric based assay. Results are shown in FIGS. 7A-7Q, 11A-11B, 12A-12F, 15A-15D, and 26A-26D.

HEK-Blue IL2 cells (InvivoGen) were plated in suspension at a concentration of 50,000 cells/well in culture media with or without 15-40 mg/ml human serum albumin (HSA) and stimulated with a dilution series of recombinant hIL2 or activatable hIL2 for 24 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved activatable hIL2 was tested. Cleaved inducible hIL2 was generated by incubation with active MMP9. IL12 activity was assessed by quantification of Secreted Alkaline Phosphatase (SEAP) activity using the reagent QUANTI-Blue (InvivoGen), a colorimetric based assay. Exemplary results are shown in FIGS. 1A-1F and FIGS. 24A-24D.

HEK-Blue IFN-α/b cells (InvivoGen) were plated in suspension at a density of 50,000 cells/well in culture media with or without 15 mg/ml human serum albumin (HSA) and stimulated with a dilution series of recombinant human IFNa (or IFNb) and activatable human IFNa (or IFNb) for 20-24 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved activatable IFNa (or IFNb) was tested. Cleaved inducible IFNa (or IFNb) was generated by incubation with active recombinant protease. Stimulation of HEK-Blue IFN-α/β cells with IFNα (or IFNβ) induces expression of Secreted Alkaline Phosphatase (SEAP) from an ISG54-SEAP reporter. IFNα (or IFNβ) activity was assessed by quantification of SEAP activity using the reagent QUANTI-Blue (InvivoGen), a colorimetric based assay. Results are shown in FIGS. 36A-36H.

Example 20: Splenocyte T-Blast Assay

T-Blasts were induced from murine splenocytes with a 6-day incubation with PHA and a 24 hr incubation with recombinant hIL12. Tblasts were then plated in suspension at a concentration of 200,000 cells/well in culture media with or without 40 mg/ml human serum albumin (HSA) and stimulated with a dilution series of recombinant hIL12 or chimeric IL12 (mouse p35/human p40) or mouse IL12 for 72 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved IL12 fusion proteins was tested. Cleaved inducible hIL12 was generated by incubation with active MMP9. IL12 activity was assessed by downstream quantification of IFNγ production using a mIFNγ alpha ELISA.

Example 21: In Vivo Delivery of a Protease Activated Fusion Protein Results in Decreased Tumor Growth

The chimeric polypeptide is examined to determine if it could have biological effects in vivo. For these experiments a system is used in which tumor cells injected intraperitoneally rapidly and preferentially attach and grow initially on the milky spots, a series of organized immune aggregates found on the omentum (Gerber et al., Am. J. Pathol. 169:1739-52 (2006)). This system offers a convenient way to examine the effects of fusion protein treatment on tumor growth since fusion proteins can be delivered intraperitoneally multiple times and tumor growth can be analyzed by examining the dissociated omental cells. For these experiments, the Colon 38 cell line, a rapidly growing tumor cell line that expresses both MMP2 and MMP9 in vitro, may be used. The omental tissue normally expresses a relatively small amount of MMP2 and MMP9, but, when Colon 38 tumor is present on the omentum, MMP levels increase. Using this tumor model, the ability of IL-2 mutein fusion proteins to affect tumor growth is examined. Colon 38 cells are injected intraperitoneally, allowed to attach and grow for 1 day, and then treated daily with fusion protein interaperitoneally. At day 7, the animals are sacrificed and the omenta examined for tumor growth using flow cytometry and by a colony-forming assay.

Example 22: Construction of an Exemplary Activatable Interleukin Protein Targeting CD20 Generation of an Activatable Interleukin Domain

The human IL-12p35 chain canonical sequence is Uniprot Accession No. P29459. The human IL-12p40 chain canonical sequence is Uniprot Accession No. P29460. IL-12p35 and IL-12p40 are cloned into an expression construct. A protease cleavage site is included between the IL-12p35 and IL-12p40 domains. An IL-12 polypeptide capable of binding to CD20 polypeptide present in a tumor or on a tumor cell is produced as follows. A nucleic acid is produced that contains nucleic acid sequences: (1) encoding an IFNγ polypeptide sequence and (2) one or more polypeptide linkers. Activatable interleukin plasmid constructs can have optional Flag, His or other affinity tags, and are electroporated into HEK293 or other suitable human or mammalian cell lines and purified. Validation assays include T cell activation assays using T cells responsive to IL-12 stimulation in the presence of a protease.

Generation of a scFv CD20 Binding Domain

CD20 is one of the cell surface proteins present on B-lymphocytes. CD20 antigen is found in normal and malignant pre-B and mature B lymphocytes, including those in over 90% of B-cell non-Hodgkin's lymphomas (NHL). The antigen is absent in hematopoietic stem cells, activated B lymphocytes (plasma cells) and normal tissue. As such, several antibodies mostly of murine origin have been described: 1F5, 2B8/C2B8, 2H7, and 1H4.

Human or humanized anti-CD20 antibodies are therefore used to generate scFv sequences for CD20 binding domains of an activatable interleukin protein. DNA sequences coding for human or humanized VL and VH domains are obtained, and the codons for the constructs are, optionally, optimized for expression in cells from Homo sapiens. The order in which the VL and VH domains appear in the scFv is varied (i.e., VL-VH, or VH-VL orientation), and three copies of the “G4S” (SEQ ID NO.: 449) or “G₄S” (SEQ ID NO.: 449) subunit (G₄S)₃ (SEQ ID NO.: 452) connect the variable domains to create the scFv domain. Anti-CD20 scFv plasmid constructs can have optional Flag, His or other affinity tags, and are electroporated into HEK293 or other suitable human or mammalian cell lines and purified. Validation assays include binding analysis by FACS, kinetic analysis using Proteon, and staining of CD20-expressing cells.

Cloning of DNA Expression Constructs Encoding the Activatable Interleukin Protein

The activatable interleukin construct with protease cleavage site domains are used to construct an activatable interleukin protein in combination with an anti-CD20 scFv domain and a serum half-life extension element (e.g., a HSA binding peptide or VH domain). For expression of an activatable interleukin protein in CHO cells, coding sequences of all protein domains are cloned into a mammalian expression vector system. In brief, gene sequences encoding the activatable interleukin domain, serum half-life extension element, and CD20 binding domain along with peptide linkers L1 and L2 are separately synthesized and subcloned. The resulting constructs are then ligated together in the order of CD20 binding domain—L1-IL-12p35-L2-protease cleavage domain—L3-IL-12p40-L4-anti-CD20 scFv-L5-serum half-life extension element to yield a final construct. All expression constructs are designed to contain coding sequences for an N-terminal signal peptide and a C-terminal hexahistidine (6×His)-tag (SEQ ID NO.: 354) to facilitate protein secretion and purification, respectively.

Expression of Activatable Interleukin Proteins in Stably Transfected CHO Cells

A CHO cell expression system (Flp-In®, Life Technologies), a derivative of CHO-K1 Chinese Hamster ovary cells (ATCC, CCL-61) (Kao and Puck, Proc. Natl. Acad Sci USA 1968; 60(4):1275-81), is used. Adherent cells are subcultured according to standard cell culture protocols provided by Life Technologies.

For adaption to growth in suspension, cells are detached from tissue culture flasks and placed in serum-free medium. Suspension-adapted cells are cryopreserved in medium with 10% DMSO.

Recombinant CHO cell lines stably expressing secreted activatable interleukin proteins are generated by transfection of suspension-adapted cells. During selection with the antibiotic Hygromycin B viable cell densities are measured twice a week, and cells are centrifuged and resuspended in fresh selection medium at a maximal density of 0.1×10⁶ viable cells/mL. Cell pools stably expressing activatable interleukin proteins are recovered after 2-3 weeks of selection at which point cells are transferred to standard culture medium in shake flasks. Expression of recombinant secreted proteins is confirmed by performing protein gel electrophoresis or flow cytometry. Stable cell pools are cryopreserved in DMSO containing medium.

Activatable interleukin proteins are produced in 10-day fed-batch cultures of stably transfected CHO cell lines by secretion into the cell culture supernatant. Cell culture supernatants are harvested after 10 days at culture viabilities of typically >75%. Samples are collected from the production cultures every other day and cell density and viability are assessed. On day of harvest, cell culture supernatants are cleared by centrifugation and vacuum filtration before further use.

Protein expression titers and product integrity in cell culture supernatants are analyzed by SDS-PAGE.

Purification of Activatable Interleukin Proteins

Activatable interleukin proteins are purified from CHO cell culture supernatants in a two-step procedure. The constructs are subjected to affinity chromatography in a first step followed by preparative size exclusion chromatography (SEC) on Superdex 200 in a second step. Samples are buffer-exchanged and concentrated by ultrafiltration to a typical concentration of >1 mg/mL. Purity and homogeneity (typically >90%) of final samples are assessed by SDS PAGE under reducing and non-reducing conditions, followed by immunoblotting using an anti-HSA or anti idiotype antibody as well as by analytical SEC, respectively. Purified proteins are stored at aliquots at −80° C. until use.

Example 23: Determination of Antigen Affinity by Flow Cytometry

The activatable interleukin proteins of Example 5 are tested for their binding affinities to human CD20⁺ cells and cynomolgus CD20⁺ cells.

CD20⁺ cells are incubated with 100 μL of serial dilutions of the activatable interleukin proteins of Example 5 and at least one protease. After washing three times with FACS buffer the cells are incubated with 0.1 mL of 10 μg/mL mouse monoclonal anti-idiotype antibody in the same buffer for 45 min on ice. After a second washing cycle, the cells are incubated with 0.1 mL of 15 μg/mL FITC-conjugated goat anti-mouse IgG antibodies under the same conditions as before. As a control, cells are incubated with the anti-His IgG followed by the FITC-conjugated goat anti-mouse IgG antibodies without the activatable interleukin proteins. The cells were then washed again and resuspended in 0.2 mL of FACS buffer containing 2 μg/mL propidium iodide (PI) in order to exclude dead cells. The fluorescence of 1×10⁴ living cells is measured using a Beckman-Coulter FC500 MPL flow cytometer using the MXP software (Beckman-Coulter, Krefeld, Germany) or a Millipore Guava EasyCyte flow cytometer using the Incyte software (Merck Millipore, Schwalbach, Germany). Mean fluorescence intensities of the cell samples are calculated using CXP software (Beckman-Coulter, Krefeld, Germany) or Incyte software (Merck Millipore, Schwalbach, Germany). After subtracting the fluorescence intensity values of the cells stained with the secondary and tertiary reagents alone the values are then used for calculation of the K_(D) values with the equation for one-site binding (hyperbola) of the GraphPad Prism (version 6.00 for Windows, GraphPad Software, La Jolla Calif. USA).

CD20 binding and crossreactivity are assessed on the human CD20⁺ tumor cell lines. The K_(D) ratio of crossreactivity is calculated using the K_(D) values determined on the CHO cell lines expressing either recombinant human or recombinant cynomolgus antigens.

Example 24: Cytotoxicity Assay

The activatable interleukin protein of Example 5 is evaluated in vitro on its mediation of immune response to CD20⁺ target cells.

Fluorescence labeled CD20⁺ REC-1 cells (a Mantle cell lymphoma cell line, ATCC CRL-3004) are incubated with isolated PBMC of random donors or CB15 T-cells (standardized T-cell line) as effector cells in the presence of the activatable interleukin protein of Example 5 and at least one protease. After incubation for 4 h at 37° C. in a humidified incubator, the release of the fluorescent dye from the target cells into the supernatant is determined in a spectrofluorimeter. Target cells incubated without the activatable interleukin protein of Example 5 and target cells totally lysed by the addition of saponin at the end of the incubation serve as negative and positive controls, respectively.

Based on the measured remaining living target cells, the percentage of specific cell lysis is calculated according to the following formula: [1−(number of living targets_((sample))/number of living targets_((spontaneous)))]×100%. Sigmoidal dose response curves and EC₅₀ values are calculated by non-linear regression/4-parameter logistic fit using the GraphPad Software. The lysis values obtained for a given antibody concentration are used to calculate sigmoidal dose-response curves by 4 parameter logistic fit analysis using the Prism software.

Example 25: Pharmacokinetics of Activatable Interleukin Proteins

The activatable interleukin protein of Example 5 is evaluated for half-time elimination in animal studies.

The activatable interleukin protein is administered to cynomolgus monkeys as a 0.5 mg/kg bolus injection into the saphenous vein. Another cynomolgus monkey group receives a comparable cytokine in size, but lacking a serum half-life extension element. A third and fourth group receive a cytokine with serum half-life extension elements and a cytokine with CD20 and serum half-life extension elements respectively, and both comparable in size to the activatable interleukin protein. Each test group consists of 5 monkeys. Serum samples are taken at indicated time points, serially diluted, and the concentration of the proteins is determined using a binding ELISA to CD20.

Pharmacokinetic analysis is performed using the test article plasma concentrations. Group mean plasma data for each test article conforms to a multi-exponential profile when plotted against the time post-dosing. The data are fit by a standard two-compartment model with bolus input and first-order rate constants for distribution and elimination phases. The general equation for the best fit of the data for i.v. administration is: c(t)=Ae^(−αt)+Be^(−βt), where c(t) is the plasma concentration at time t, A and B are intercepts on the Y-axis, and α and β are the apparent first-order rate constants for the distribution and elimination phases, respectively. The α-phase is the initial phase of the clearance and reflects distribution of the protein into all extracellular fluid of the animal, whereas the second or β-phase portion of the decay curve represents true plasma clearance. Methods for fitting such equations are well known in the art. For example, A=DN(α−k21)/(α−β), B=DN(β−k21)/(α−β), and α and β (for α>β) are roots of the quadratic equation: r2+(k12+k21+k10)r+k21k10=0 using estimated parameters of V=volume of distribution, k10=elimination rate, k12=transfer rate from compartment 1 to compartment 2 and k21=transfer rate from compartment 2 to compartment 1, and D=the administered dose.

Data analysis: Graphs of concentration versus time profiles are made using KaleidaGraph (KaleidaGraph™ V. 3.09 Copyright 1986-1997. Synergy Software. Reading, Pa.). Values reported as less than reportable (LTR) are not included in the PK analysis and are not represented graphically. Pharmacokinetic parameters are determined by compartmental analysis using WinNonlin software (WinNonlin® Professional V. 3.1 WinNonlin™ Copyright 1998-1999. Pharsight Corporation. Mountain View, Calif.). Pharmacokinetic parameters are computed as described in Ritschel W A and Kearns G L, 1999, IN: Handbook Of Basic Pharmacokinetics Including Clinical Applications, 5th edition, American Pharmaceutical Assoc., Washington, D.C.

It is expected that the activatable interleukin protein of Example 5 has improved pharmacokinetic parameters such as an increase in elimination half-time as compared to proteins lacking a serum half-life extension element.

Example 26: Xenograft Tumor Model

The activatable interleukin protein of Example 5 is evaluated in a xenograft model.

Female immune-deficient NOD/scid mice are sub-lethally irradiated (2 Gy) and subcutaneously inoculated with 4×10⁶ Ramos RA1 cells into the right dorsal flank. When tumors reach 100 to 200 mm³, animals are allocated into 3 treatment groups. Groups 2 and 3 (8 animals each) are intraperitoneally injected with 1.5×10⁷ activated human T-cells. Three days later, animals from Group 3 are subsequently treated with a total of 9 intravenous doses of 50 μg activatable interleukin protein of Example 5 (qd×9d). Groups 1 and 2 are only treated with vehicle. Body weight and tumor volume are determined for 30 days.

It is expected that animals treated with the activatable interleukin protein of Example 5 have a statistically significant delay in tumor growth in comparison to the respective vehicle-treated control group.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Example 27: MC38 Experiments

The MC38 cell line, a rapidly growing colon adenocarcinoma cell line that expresses MMP9 in vitro, was used. Using this tumor model, the ability of fusion proteins to affect tumor growth was examined.

Example 27a: MC38 IL-2POC

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 10 Vehicle — ip biwk × 3 2 7 ACP16 700 μg/animal ip biwk × 3 3 7 ACP16 230 μg/animal ip biwk × 3 4 7 ACP16 70 μg/animal ip biwk × 3 5 7 ACP16 55 ug/animal ip biwk × 3 6 7 ACP16 17 μg/animal ip biwk × 3 7 7 ACP132 361 μg/animal ip biwk × 3 8 7 ACP132 119 μg/animal ip biwk × 3 9 7 ACP132 36 μg/animal ip biwk × 3 10  7 ACP132 28 μg/animal ip biwk × 3 11  7 ACP132 9 μg/animal ip biwk × 3 12  7 ACP21 540 μg/animal ip biwk × 3 13  7 ACP21 177 μg/animal ip biwk × 3 14  7 ACP21 54 μg/animal ip biwk × 3 15  7 ACP21 42 μg/animal ip biwk × 3 16  7 ACP21 13 μg/animal ip biwk × 3 ^(#)ControlGroup

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. 308 CR female C57BI/6 mice were set up with 5×10⁵ MC38 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized.

Results are shown in FIG. 35 .

Example 27b: MC38 IL-2 POC. Treatment with ACP16, ACP124 and ACP130

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 12 Vehicle — ip biwk × 2 2 8 ACP16 4.4 μg/animal ip biwk × 2 3 8 ACP16 17 μg/animal ip biwk × 2 4 8 ACP16 70 μg/animal ip biwk × 2 5 8 ACP16 232 μg/animal ip biwk × 2 6 8 ACP130 19 μg/animal ip biwk × 2 7 8 ACP130 45 μg/animal ip biwk × 2 8 8 ACP130 180 μg/animal ip biwk × 2 9 8 ACP130 600 μg/animal ip biwk × 1 12  8 ACP124 17 μg/animal ip biwk × 2 13  8 ACP124 70 μg/animal ip biwk × 2 14  8 ACP124 230 μg/animal ip biwk × 2 15  8 ACP124 700 μg/animal ip biwk × 2 16  8 IL-2- 12 μg/animal ip bid × 5 then 2-day WTI pause then bid × 5 then 2-day pause 17  8 IL-2- 36 μg/animal ip bid × 5 then 2-day WTI pause then bid × 5 then 2-day pause ^(#)ControlGroup

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. 308 CR female C57BL/6 mice were set up with 5×10⁵ MC38 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized.

Results are shown in FIG. 31A-31C and FIG. 32B-32C. Survival curves are shown in FIGS. 34A-34D.

Example 27c: MC38 IFNa and IL-12

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 12 Vehicle — ip biwk × 3 2 8 ACP11 17.5 μg/animal ip biwk × 3 3 8 ACP11 175 μg/animal ip biwk × 3 4 8 ACP11 525 μg/animal ip biwk × 3 5 8 ACP31 33 μg/animal ip biwk × 3 6 8 ACP31 110 μg/animal ip biwk × 3 7 8 ACP31 330 μg/animal ip biwk × 3 8 8 ACP131 1 μg/animal ip bid × 5 then 2-day pause then bid × 5 then 2-day pause 9 8 ACP131 10 μg/animal ip bid × 5 then 2-day pause then bid × 5 then 2-day pause 10  8 ACP131 30 μg/animal ip bid × 5 then 2-day pause then bid × 5 then 2-day pause 11  8 mIFNa1- 1 μg/animal ip bid × 5 then 2-day WTI pause then bid × 5 then 2-day pause 12  8 mIFNa1- 10 μg/animal ip bid × 5 then 2-day WTI pause then bid × 5 then 2-day pause 13  8 IL-12- 2 μg/animal ip bid × 5 then 2-day HM- pause then bid × 5 WTI then 2-day pause 14  8 IL-12- 10 μg/animal ip bid × 5 then 2-day HM- pause then bid × 5 WTI then 2-day pause 15  8 ACP131 5 μg/animal itu bid × 5 then 2-day pause then bid × 5 then 2-day pause ^(#)ControlGroup

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. 308 CR female C57BL6 mice were set up with 5×10⁵ MC38 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized. Results are show in in FIGS. 29A-29B, and 30 .

Example 27d: Treatment with ACP16, ACP132, and ACP21

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 10 Vehicle — ip biwk × 2 2 7 ACP16 17 μg/animal ip biwk × 2 3 7 ACP16 55 μg/animal ip biwk × 2 4 7 ACP16 70 μg/animal ip biwk × 2 5 7 ACP16 230 μg/animal ip biwk × 2 6 7 ACP132 9 μg/animal ip biwk × 2 7 7 ACP132 28 μg/animal ip biwk × 1 8 7 ACP132 36 μg/animal ip biwk × 1 9 7 ACP132 119 μg/animal ip biwk × 1 10  7 ACP21 13 μg/animal ip biwk × 2 11  7 ACP21 42 μg/animal ip biwk × 2 12  7 ACP21 54 μg/animal ip biwk × 2 13  7 ACP21 177 μg/animal ip biwk × 2

Procedure

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. ACP16 was dosed at 17, 55, 70, or 230 μg/animal; ACP132 was dosed at 9, 28, 36, or 119 ug/animal; ACP21 was dosed at 13, 42, 54, or 177 μg/animal. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized. Results are shown in FIG. 35 .

Example 27e: MC38 Rechallenge

Cured mice (ACP16-treated) from Example 27b were rechallenged with tumor implantation to determine whether anti-tumor memory had been established from the initial treatments.

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 33 No — — — Treatment 2 7 ACP16 70 μg/animal ip (ACP16 biwk × 2) 3 8 ACP16 232 μg/animal ip (ACP16 biwk × 2) 5 5 IL-2-WTI 12 μg/animal ip (IL-2-WTI bid × 5 then 2-day pause then bid × 5 then 2-day pause) 6 7 IL-2-WTI 36 μg/animal ip (IL-2-WTI bid × 5 then 2-day pause then bid × 5 then 2-day pause) ^(#)ControlGroup

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. This portion of the study began on the day of implant (Day 1). Group 1 consisted of 33 CR female C57BL6 mice set up with 5×10⁵ MC38 tumor cells in 0% Matrigel subcutaneously in the flank. Groups 2-6 consisted of 33 CR female C57BI/6 mice set up with 5×10⁵ MC38 tumor cells in 0% Matrigel sc in the left flank. The tumors from the previous MC38 experiment (Example 27b) were implanted in the right flank of each animal. Cell Injection Volume was 0.1 mL/mouse. Age of control mice at initiation was 14 to 17 weeks. These mice were age matched to mice from the previous MC38 experiment (Example 27b). No dosing of active agent occurred during rechallenge. Body Weights were take biweekly until end, as were caliper measurements. Any adverse reactions or death were reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1000 mm³ or 45 days, whichever comes first. Responders were followed longer when possible. When the endpoint is reached, the animals were euthanized. Results are shown in FIG. 33 .

Example 27f: Treatment with ACP10, ACP11

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 12 Vehicle — ip biwk × 2 2 8 ACP11 175 μg/animal ip biwk × 2 3 8 ACP11 300 μg/animal ip biwk × 2 4 8 ACP10 5 μg/animal ip biwk × 2 5 8 ACP10 10 μg/animal ip biwk × 2 6 8 ACP10 43 μg/animal ip biwk × 2 7 8 ACP10 43 μg/animal ip qwk × 2 8 8 ACP10 172 μg/animal ip biwk × 2 9 8 IL-12- 5 μg/animal ip bid for 5 days HM-WTI first day 1 dose then 2-day pause then bid for 5 days first day 1 dose then 2-day pause 10  8 IL-12- 20 μg/animal ip bid for 5 days HM-WTI first day 1 dose then 2-day pause then bid for 5 days first day 1 dose then 2-day pause

Procedures

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. ACP11 was dosed at 175 or 300 μg/animal; ACP10 was dosed at 5, 10, 43, or 172 ug/animal; IL-12-HM-WTI was dosed at 5 or 20 ug/animal. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized. Results are shown in FIG. 45 and FIGS. 46A-46D.

Example 27g: Treatment with ACP16, APC153, ACP155, ACP156 and ACP292

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 12 Vehicle — ip biwk × 2 2 8 ACP16 17 μg/animal ip biwk × 2 3 8 ACP16 55 μg/animal ip biwk × 2 4 8 ACP16 230 μg/animal ip biwk × 2 5 8 ACP155 55 μg/animal ip biwk × 2 6 8 ACP155 230 μg/animal ip biwk × 2 7 8 ACP153 55 μg/animal ip biwk × 2 8 8 ACP153 230 μg/animal ip biwk × 2 9 8 ACP156 55 μg/animal ip biwk × 2 10  8 ACP156 230 μg/animal ip biwk × 2 11  8 ACP292 45 μg/animal ip biwk × 2 12  8 ACP292 186 μg/animal ip biwk × 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. ACP16 was dosed at 17, 55 or 230 μg/animal; ACP153, ACP155 and ACP156 were dosed at 55 or 230 μg/animal; ACP292 was dosed at 45 or 186 μg/animal. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized. Results are shown in FIGS. 49A-49I.

Example 27h: Treatment with ACP16, APC302 and ACP314

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 12 Vehicle — ip biwk × 2 2 9 ACP16 55 μg/animal ip biwk × 2 3 9 ACP16 230 μg/animal ip biwk × 2 4 9 ACP302 33 μg/animal ip biwk × 2 5 9 ACP302 106 μg/animal ip biwk × 2 6 9 ACP302 442 μg/animal ip biwk × 2 7 9 ACP302 1,344 μg/animal ip biwk × 2 8 9 ACP314 21 μg/animal ip biwk × 2 9 9 ACP314 68 μg/animal ip biwk × 2 10  9 ACP314 283 μg/animal ip biwk × 2 11  9 ACP314 861 μg/animal ip biwk × 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. ACP16 was dosed at 55 or 230 μg/animal; ACP302 was dosed at 33, 106, 442 or 1344 ug/animal; ACP314 was dosed at 21, 68, 283 or 861 μg/animal. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized. Results are shown in FIG. 50A-50B.

Example 27i: Treatment with ACP339

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 12 Vehicle — ip biwk × 2 2 9 ACP339 55 μg/animal ip biwk × 2 3 9 ACP339 230 μg/animal ip biwk × 2 4 9 ACP339 700 μg/animal ip biwk × 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. CR female C57BL/6 mice were set up with 5×10⁵ MC38 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. ACP339 was dosed at 55, 230 or 700 μg/animal. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized. Results are shown in FIGS. 51A-51C.

Example 28: CT26 Experiments

The CT26 cell line, a rapidly growing colon adenocarcinomacell line that expresses MMP9 in vitro, was used. Using this tumor model, the ability of fusion proteins to affect tumor growth was examined.

Example 28a: Treatment with ACP16 Alone or in Combination with Anti-PD1 Antibody

Agents and Treatment: Formulation Gr. N Agent dose Route Schedule  1^(#) 12 vehicle 1 // na // ip // days 1, 4, 8, 11 // vehicle 2 na ip days 3, 6, 10, 13 2 10 vehicle 1 // na // ip // days 1, 4, 8, 11 // ACP16 70 μg/animal ip days 3, 6, 10, 13 3 10 vehicle 1 // na // ip // days 1, 4, 8, 11 // ACP16 232 μg/animal ip days 3, 6, 10, 13 4 10 vehicle 1 // na // ip // days 1, 4, 8, 11 // ACP16 500 μg/animal ip days 3, 6, 10, 13 5 10 anti-PD-1 200 μg/animal // ip // days 1, 4, 8, 11 // RMP1-14 // na ip days 3, 6, 10, 13 vehicle 2 6 10 anti-PD-1 200 μg/animal // ip // days 1, 4, 8, 11 // RMP1-14 // 70 μg/animal ip days 3, 6, 10, 13 ACP16 7 10 anti-PD-1 200 μg/animal // ip // days 1, 4, 8, 11 // RMP1-14 // 232 μg/animal ip days 3, 6, 10, 13 ACP16 8 10 anti-PD-1 200 μg/animal // ip // days 1, 4, 8, 11 // RMP1-14 // 500 μg/animal ip days 3, 6, 10, 13 ACP16 9 10 vehicle 1 // na // ip // days 1, 4, 8, 11 // IL-2 12 μg/animal ip bid × 5 first day 1 dose per week × 2 10  10 anti-PD-1 200 μg/animal // ip // days 1, 4, 8, 11 // RMP1-14 // 12 μg/animal ip bid × 5 first day 1 IL-2 dose per week × 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. CR female BALB/c mice were set up with 3×10⁵ CT26 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. ACP 16 was dosed at 70, 230 or 500 μg/animal with or without anti-PD-1 antibody (RMP1-14) at 200 μg/animal. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized. Results are shown in FIGS. 47A-47D and FIGS. 48A-48B.

Example 29. Human Tblast Assay

IL-2 T-Blast Assay. Pre-stimulated T cells (T-blasts) were used to assess the activity of inducible IL-2 fusion proteins. T-Blasts were induced from human PBMCs with a 3-day incubation with PHA. Tblasts were then plated in suspension at a concentration of 50,000 or 75,000 cells/well in X-VIVO culture media (containing human serum albumin) and stimulated with a dilution series of recombinant IL-2 fusion proteins or human IL-2 for 72 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved IL-2 fusion proteins was tested. Cleaved inducible IL-2 was generated by incubation with active MMP9. IL-2 activity was assessed measuring proliferation with CellTiter-Glo. Exemplary results are shown in FIG. 3A-3I.

IL-12 T-Blast Assay. T-Blasts were induced from human PBMCs through PHA stimulation for 72 hours. T-blasts were then washed and frozen prior use. For the assay, T-Blasts were thaw and plated in suspension at 100,000 cells/well in culture media containing human albumin and stimulated with a dilution series of recombinant hIL12 or chimeric IL12 (mouse p35/human p40) indukines or hIL12 indukines for 72 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved IL12 fusion proteins was tested. Cleaved inducible hIL12 was generated by incubation with active MMP9 enzyme. IL12 activity was assessed by quantification of IFNγ production in supernatants using a hIFNγ Alpha-LISA kit. Exemplary results are shown in FIGS. 8A-8D.

Example 30. Luciferase Reporter Assay

IL-2 luciferase reporter cells (Promega), purchased from the manufacturer in a “Thaw and Use” format, were plated according to the manufacturer's directions and stimulated with a dilution series of recombinant hIL-2 or activatable hIL-2 for 6 hours at 37° C. and 5% CO2. Activity of uncleaved and cleaved activatable IL-2 was tested. Cleaved inducible IL-2 was generated by incubation with active MMP9. IL-2 activity was assessed by quantification of luciferase activity using Bio-Glo™ Reagent (Promega), which allows for the measurement of luciferase activity by luminescence readout. Results are shown in FIGS. 2A-2J.

IL12 luciferase reporter cells (Promega), purchased from the manufacturer in a “Thaw and Use” format, were plated according to the manufacturer's directions and stimulated with a dilution series of recombinant hIL12 or activatable hIL12 for 6 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved activatable IL12 was tested. Cleaved inducible IL12 was generated by incubation with active MMP9. IL12 activity was assessed by quantification of luciferase activity using Bio-Glo™ Reagent (Promega), which allows for the measurement of luciferase activity by luminescence readout. Results are shown in FIGS. 9A-9C.

Example 31. MC38 Experiments

Agents and Treatment: Group N Agent Dose Route Schedule 1 12 vehicle — ip biwk × 2 2 8 WW0417 55 μg/animal ip biwk × 2 3 8 WW0517 55 μg/animal ip biwk × 2 4 8 WW0517 230 μg/animal ip biwk × 2 5 8 WW0517 700 μg/animal ip biwk × 2 6 8 WWW0520/0523 76 μg/animal ip biwk × 2 7 8 WWW0520/0523 315 μg/animal ip biwk × 2 8 8 WWW0520/0523 959 μg/animal ip biwk × 2 9 8 WWW0548/0524 88 μg/animal ip biwk × 2 10 8 WWW0548/0524 368 μg/animal ip biwk × 2 11 8 WWW0548/0524 1,120 μg/animal ip biwk × 2 12 8 WWW0548/0556 113 μg/animal ip biwk × 2 13 8 WWW0548/0556 474 μg/animal ip biwk × 2 14 8 WWW0548/0556 1,442 μg/animal ip biwk × 2 15 8 WW0475 68 μg/animal ip biwk × 2 16 8 WW0475 283 μg/animal ip biwk × 2 17 8 WW0475 861 μg/animal ip biwk × 2 10 8 WW0619 17 μg/animal ip biwk × 2 11 8 WW0619 35 μg/animal ip biwk × 2 12 8 WW0619 70 μg/animal ip biwk × 2 13 8 WW0619 700 μg/animal ip biwk × 2 14 8 WW0621/0523 24 μg/animal ip biwk × 2 15 8 WW0621/0523 48 μg/animal ip biwk × 2 16 8 WW0621/0523 96 μg/animal ip biwk × 2 17 8 WW0621/0523 960 μg/animal ip biwk × 2

Procedures:

Mice were anaesthetized with isoflurane for implant of cells to reduce the ulcerations. 308 CR female C57BL/6 mice were set up with 5×10 MC38 tumor cells in 0% Matrigel sc in flank. Cell Injection Volume was 0.1 mL/mouse. Mouse age at start date was 8 to 12 weeks. Pair matches were performed when tumors reach an average size of 100-150 mm³ and begin treatment. Body weights were taken at initiation and then biweekly to the end. Caliper measurements were taken biweekly to the end. Any adverse reactions were to be reported immediately. Any individual animal with a single observation of >than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. Any group with a mean body weight loss of >20% or >10% mortality stopped dosing; the group was not euthanized, and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint were euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery were allowed on a case-by-case basis. Endpoint was tumor growth delay (TGD). Animals were monitored individually. The endpoint of the experiment was a tumor volume of 1500 mm³ or 45 days, whichever comes first. Responders were followed longer. When the endpoint was reached, the animals are to be euthanized. Results are shown in FIGS. 4-6 .

Sample fusion protein constructs are detailed in Table 3. In table 3, “L” is an abbreviation of “linker”, and “cleav. link.” is an abbreviation of “cleavable linker”. Other abbreviations “mIFNg” indicates mouse interferon gamma (IFNg); “hAlbumin” indicates human serum albumin (HSA); “mAlbumin” indicates mouse serum albumin.

Example 32. Human Interferon PBMC Assay

Human PBMCs were isolated form blood obtained from healthy donors. After isolation, PBMCs were cryopreserved until the assay was performed. For the assay, PBMCs were thawed and plated in suspension at 100,000 cells/well in X-Vivo media supplemented with 1.5% of human serum albumin. % well round bottom plates were used for the assay. Cells were stimulated with a dilution series of recombinant human IFNα and activatable human IFNα for 48 hours at 37° C. and 5% CO₂. Activity of uncleaved and cleaved activatable IFNα was tested. Cleaved inducible IFNα was generated by incubation with active recombinant protease. PBMC supernatants were collected and amounts of CXCL-10 (IP-10) produced were quantified using AlphaLISA as a measure of response. Results are shown in FIGS. 38A-38C.

TABLE 3 CONSTRUCT PERMUTATION TABLE (“6xHis” disclosed as SEQ ID NO: 354) Construct Name Construct Description ACP01 (anti-HSA)-(cleav. link.)-mouse IFNg-(cleav. link.)-(anti-HSA)-6xHis ACP02 (anti-HSA)-(cleav. link.)-mouse IFNg-(cleav. link.)-mouse IFNg-(cleav. link.)-(anti-HSA)- 6xHis ACP03 (anti-HSA)-(cleav. link.)-mouse IFNg-mouse IFNg-(cleav. link.)-(anti-HSA)-6xHis ACP50 (anti-EpCAM)-(anti-HSA)-(cleav. link.)-mouse IFNg-mouse IFNg-(cleav. link.)-(anti-HSA)- 6xHis ACP51 (anti-EpCAM)-Linker-(anti-HSA)-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-6xHis ACP52 (anti-HSA)-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-Linker-(anti-EpCAM)-6xHis ACP53 mAlbumin-(cleav. link.)-mIFNg-(cleav. link.)-mAlbumin-6xHis ACP54 mAlbumin-(cleav. link.)-mIFNg-Linker-mIFNg-(cleav. link.)-mAlbumin-6xHis ACP30 (anti-HSA)-(cleav. link.)-mouse IFNg-(cleav. link.)-(anti-HSA)-(cleav. link.)-mouse IFNg- (cleav. link.)-(anti-HSA)-6xHis ACP55 (anti-HSA)-(cleav. link.)-mouse IFNg-(cleav. link.)-(anti-HSA)-(cleav. link.)-mouse IFNg- (cleav. link.)-(anti-HSA)-6xHis-C-tag ACP56 (anti-FOLR1)-Linker-(anti-HSA)-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-6xHis ACP57 (anti-HSA)-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-Linker-(anti-FOLR1)-6xHis ACP58 (anti-HSA)-(cleav. link.)-mIFNg-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-Linker-(anti- EpCAM)-6xHis ACP59 (anti-FOLR1)-Linker-(anti-HSA)-(cleav. link.)-mIFNg-(cleav. link.)-mIFNg-(cleav. link.)- (anti-HSA)-6xHis ACP60 (anti-HSA)-(cleav. link.)-mIFNg-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-Linker-(anti- FOLR1)-6xHis ACP61 (anti-HSA)-(cleav. link.)-mIFNg-(cleav. link.)-mIFNg-(cleav. link.)-(anti-HSA)-Linker- FN(CGS-2)-6xHis ACP63 anti-FN CGS-2 scFv (Vh/Vl)-6xHis ACP69 (anti-HSA)-(cleav. link.)-mouse IFNg-(cleav. link.)-(anti-HSA)-(cleav. link.)-mouse IFNg ACP70 mouse IFNg-(cleav. link.)-(anti-HSA)-(cleav. link.)-mouse IFNg-(cleav. link.)-(anti-HSA) ACP71 mouse IFNg-(cleav. link.)-mAlbumin-(cleav. link.)-mouse IFNg-(cleav. link.)-mAlbumin ACP72 mAlbumin-(cleav. link.)-mouse IFNg-(cleav. link.)-mAlbumin-(cleav. link.)-mouse IFNg ACP73 mAlbumin-(cleav. link.)-mouse IFNg-(cleav. link.)-mAlbumin-(cleav. link.)-mouse IFNg- (cleav. link.)-mAlbumin ACP74 mAlbumin-(cleav. link.)-mouse IFNg-(cleav. link.)-5mer linker-mAlbumin-5mer linker-(cleav. link.)-mouse IFNg-(cleav. link.)-mAlbumin ACP75 mAlbumin-(cleav. link.)-mouse IFNg-(cleav. link.)-10mer linker-mAlbumin-10mer linker- (cleav. link.)-mouse IFNg-(cleav. link.)-mAlbumin ACP78 (anti-HSA)-Linker-mouse_IFNg-Linker-(anti-HSA)-Linker-mouse_IFNg-Linker-(anti- HSA)_(non-cleavable_control) ACP134 Anti-HSA-(cleav. link.)-mouse_IFNg-(cleav. link.)-anti-HSA-(cleav. link.)-mouse_IFNg- (cleav. link.)-anti-HSA-L-anti-FOLR1 ACP135 Anti-FOLR1-L-HSA-(cleav. link.)-mouse_IFNg-(cleav. link.)-HSA-(cleav. link.)-mouse_IFNg- (cleav. link.)-HSA ACP04 human p40-murine p35-6xHis ACP05 human p40-human p35-6xHis ACP34 mouse p35-(cleav. link.)-mouse p40-6xHis ACP35 mouse p35-GS-(cleav. link.)-GS-mouse p40-6xHis ACP36 (anti-HSA)-(Cleav. Linker)-mouse p40-mouse p35-(Cleav. Linker)-(anti-HSA)-6xHis ACP37 (anti-EpCAM)-(anti-HSA)-(Cleav. Linker)-mouse p40-mouse p35-(Cleav. Linker)-(anti-HSA)- 6xHis ACP79 (anti-EpCAM)-Linker-(anti-HSA)-(cleav. link.)-mIL12-(cleav. link.)-(Anti-HSA)-6xHis ACP80 (anti-HSA)-(cleav. link.)-mIL12-(cleav. link.)-(anti-HSA)-Linker-(anti-EpCAM)-6xHis ACP06 Blocker12-Linker-(cleav. link.)-human p40-Linker-mouse p35-(cleav. link.)-(anti-HSA)-6xHis ACP07 Blocker12-Linker-(cleav. link.)-human p40-Linker-mouse p35-(cleav. link.)-(anti-HSA)- Linker-(anti-FOLR1)-6xHis ACP08 (anti-FOLR1)-Linker-Blocker12-Linker-(cleav. link.)-human p40-Linker-mouse p35-(cleav. link.)-(anti-HSA)-6xHis ACP09 (anti-HSA)-Linker-Blocker12-Linker-(cleav. link.)-human p40-Linker-mouse p35-6xHis ACP10 (anti-HSA)-(cleav. link.)-human p40-L-mouse p35-(cleav. link.)-Linker-Blocker12-6xHis ACP11 Human_p40-Linker-mouse_p35-(cleav. link.)-Linker-Blocker12-Linker-(anti-HSA)-6xHis ACP91 human_p40-Linker-mouse_p35-Linker-Linker-Blocker-Linker-(anti-HSA)_(non- cleavable_control) ACP136 human p40-L-mouse p35-(cleav. link.)-Blocker ACP138 human_p40-L-mouse_p35-(cleav. link.)-Blocker-L-(anti-HSA)-L-FOLR1 ACP139 Anti-FOLR1-L-human_p40-L-mouse_p35-(cleav. link.)-Blocker12-L-(anti-HSA) ACP140 Anti-FOLR1-(cleav. link.)-human_p40-L-mouse_p35-(cleav. link.)-Blocker12-L-(anti-HSA) ACP12 (anti-EpCAM)-IL2-(cleav. link.)-(anti-HSA)-blocker2-6xHis ACP13 (anti-EpCAM)-Blocker2-(anti-HSA)-(cleav. link.)-IL2-6xHis ACP14 Blocker2-Linker-(cleav. link.)-IL2- (cleav. link.)-(anti-HSA)-6xHis (WW0045) ACP15 Blocker2-Linker-(anti-HSA)-Linker-(cleav. link.)- IL2 -6xHis (WW0047) ACP16 IL2-(cleav. link.)-(anti-HSA)-Linker-(cleav. link.)-Blocker2-6xHis (WW0048) ACP17 (anti-EpCAM)-Linker-IL2-(cleav. link.)-(anti-HSA)-Linker-(cleav. link.)-Blocker2-6xHis ACP18 (anti-EpCAM)-Linker-IL2-(cleav. link.)-(anti-HSA)-Linker-vh(cleav. link.)vl-6xHis ACP19 IL2-(cleav. link.)-Linker-Blocker2-Linker-(anti-HSA)-Linker-(anti-EpCAM) -6xHis ACP20 IL2-(cleav. link.)-Blocker2-6xHis (WW0056) ACP21 IL2-(cleav. link.)-Linker-Blocker2-6xHis (WW0057) ACP22 IL2-(cleav. link.)-Linker-blocker-(cleav. link.)-(anti-HSA)-Linker-(anti-EpCAM)-6xHis ACP23 (anti-FOLR1)-(cleav. link.)-Blocker2-Linker-(cleav. link.)-(anti-HSA)-(cleav. link.)- IL2-6xHis ACP24 (Blocker2)-(cleav. link.)-(IL2)-6xHis (WW0074) ACP25 Blocker2-Linker-(cleav. link.)-IL2-6xHis (WW0075) ACP26 (anti-EpCAM)-Linker-IL2-(cleav. link.)-(anti-HSA)-Linker-blocker(NARA1 Vh/Vl) ACP27 (anti-EpCAM)-Linker-IL2-(cleav. link.)-(anti-HSA)-Linker-blocker(NARA1 Vl/Vh) ACP28 IL2-(cleav. link.)-Linker-Blocker2-(NARA1 Vh/Vl)-Linker-(anti-HSA)-Linker-(anti-EpCAM) ACP29 IL2-(cleav. link.)-Linker-Blocker2-(NARA1 Vl/Vh)-Linker-(anti-HSA)-Linker-(anti-EpCAM) ACP38 IL2-(cleav. link.)-blocker-(anti-HSA)-(anti-EpCAM)-6xHis ACP39 (anti-EpCAM)-(cleav. link.)-(anti-HSA)-(cleav. link.)-Blocker2-(cleav. link.)-IL-2-6xHis ACP40 CD25ecd-Linker-(cleav. link.)-IL2-6xHis (WW0076) ACP41 IL2-(cleav. link.)-Linker-CD25ecd-6xHis (WW0077) ACP42 (anti-HSA)-Linker-CD25ecd-Linker-(cleav. link.)-IL2-6xHis (WW0078) ACP43 IL2-(cleav. link.)-Linker-CD25ecd-Linker-(anti-HSA)-6xHis (WW0079) ACP44 IL2-(cleav. link.)-Linker-CD25ecd-(cleav. link.)-(anti-HSA)-6xHis (WW0080) ACP45 (anti-HSA)-(cleav. link.)-Blocker2-Linker-(cleav. link.)-IL2-6xHis (WW0046) ACP46 IL2-(cleav. link.)-linkerL-vh(cleav. link.)vl-Linker-(anti-HSA)-L-(anti-EpCAM)-6xHis ACP47 (anti-EpCAM)-Linker-IL2-(Cleavable Linker)-(anti-HSA)-Linker-Blocker2-6xHis ACP48 IL2-(cleav. link.)-Blocker2-Linker-(anti-HSA)-6xHis (WW0054) ACP49 IL2-(cleav. link.)-Linker-Blocker2-Linker-(anti-HSA)-6xHis (WW0055) ACP92 (anti-HSA)-(16mer Cleav. Link.)-IL2-(16mer Cleav. Link.)-(anti-HSA)-6XHis ACP93 (anti-EpCAM)-(anti-HSA)-(anti-EpCAM)-Blocker2-(cleav. link.)-IL2-6xHis ACP94 (anti-EpCAM)-(anti-HSA)-Blocker2-(cleav. link.)-IL2-6xHis ACP95 (anti-EpCAM)-(anti-HSA)-(cleav. link.)-IL2-6xHis ACP96 (anti-EpCAM)-(16mer cleav. link.)-IL2-(16mer cleav. link.)-(anti-HSA) ACP97 (anti-EpCAM)-(anti-HSA)-(cleav. link.)-IL2-(cleav. link.)-(anti-HSA)-6xHis ACP99 (anti-EpCAM)-Linker-IL2-(cleav. link.)-(anti-HSA)-6xHis ACP100 (anti-EpCAM)-Linker-IL2-6xHis ACP101 IL2-(cleav. link.)-(anti-HSA)-6xHis (WW0061) ACP102 (anti-EpCAM)-(cleav. link.)-IL2-(cleav. link.)-(anti-HSA)-Linker-blocker-6xHis ACP103 IL2-(cleav. link.)-Linker-Blocker2-Linker-(anti-HSA)-Linker-(antiI-FOLR1)-6xHis ACP104 (anti-FOLR1)-IL2-(cleav. link.)-(anti-HSA)-Linker-Blocker2-6xHis ACP105 Blocker2-Linker-(cleav. link.)-IL2-(cleav. link.)-(anti-HSA)-Linker-(anti-FOLR1)-6xHis ACP106 (anti-FOLR1)-Linker-(anti-HSA)-(cleav. link.)-blocker-Linker-(cleav. link.)-IL2 -6xHis ACP107 Blocker2-Linker-(anti-HSA)-(cleav. link.)-IL2-Linker-(anti-FOLR1)-6xHis ACP108 (anti-EpCAM)-IL2-(Dually cleav. link.)-(anti-HSA)-Linker-blocker-6xHis ACP117 anti-FN CGS-2 scFv (Vh/Vl)-6xHis ACP118 NARA1 Vh/Vl non-cleavable ACP119 NARA1 Vh/Vl cleavable ACP120 NARA1 Vl/Vh non-cleavable ACP121 NARA1 Vl/Vh cleavable ACP124 IL2-Linker-(anti-HSA)-Linker-Linker-blocker_(non-cleavable_control) (WW0159) ACP132 IL2-L-HSA (WW0177) ACP141 IL2-L-human_Albumin (WW0178) ACP142 IL2-(cleav. link.)-human_Albumin (WW0179) ACP144 IL2-(cleav. link.)-HSA-(cleav.-link.)blocker-L-(anti-FOLR1) ACP145 Anti-FOLR1-L-IL2-(cleav. link.)-HSA-Linker-(cleav. link.)-blocker2 ACP146 Anti-FOLR1-(cleav. link)-IL2-(cleav. link.)-HSA-Linker-(cleav. link.)-blocker2 ACP133 IL2-6x His (WW0196) ACP147 IL2-(cleav. Linker)-(anti-HSA)-Linker-(cleav. link.)-blocker2-L-(anti-EpCAM) ACP148 (anti-EpCAM)-L-IL2-(cleav. link.)-(anti-HSA)-L-(cleav. Linker)-blocker2 ACP149 (anti-EpCAM)-(cleav. link.)-IL2-(cleav. Linker)-(anti-HSA)-L-(cleav. Linker)-blocker2 ACP31 (anti-HSA)-(cleav. link.)-mIFNa1-(cleav. link.)-(anti-HSA) ACP32 (anti-HSA)-(cleav. link.)-mIFNa1(N + C trunc)-(cleav. link.)-(anti-HSA) ACP33 (anti-HSA)-(cleav. link.)-mIFNa1(C trunc)-(cleav. link.)-(anti-HSA) ACP131 mIFNa1 ACP125 Anti-HSA-(cleav. link.)-mIFNa1 ACP126 mIFNa1-(cleav. link.)-(anti-HSA) ACP127 Mouse_Albumin-(cleav. Link.)-mIFNa1-(cleav link)-mouse_Albumin ACP128 Mouse_Albumin-(cleav. link.)-mIFNa1 ACP129 mIFNa1-(cleav. link.)-mAlb ACP150 (Anti-FOLR1)-L-(anti-HSA)-(cleav. Link.)-mIFNa1-(cleav. Link.)-(anti-HSA) ACP151 Anti-FOLR1-L-(anti-HSA)-(cleav. Link.)-mIFNa1-(cleav. Link.)-(anti-HSA)-L-(anti-FOLR1) ACP152 (anti-HSA)-L-mIFNa1-L-(anti-HSA)_(non-cleavable_control) ACP153 IL2-(cleav. link.)-(anti-HSA)-linker(cleav. link.)-blocker2 (WW0201) ACP154 IL2-(cleav. link.)-(anti-HSA)-linker(cleav. link.)-blocker2 (WW0202) ACP155 IL2-(cleav. link.)-(anti-HSA)-linker(cleav. link.)-blocker2 (WW0203) ACP156 IL2-X-anti-HSA-LX-blocker_(X = Linker4_Blocker = Vh-Vl) (WW0204) ACP157 IL2-X-anti-HSA-LX-blocker_(X = Linker5_Blocker = Vh-Vl) (WW0205) ACP200 mAlb(D3)-X-mouse-IFNa-X-mAlb(D3)_(X = Linker 1) ACP201 mAlb(D1-L-D3)-X-mouse-IFNa-X-mAlb(D1-L-D3)_(X = Linker 1) ACP202 HSA-X-mIFNa1-X-HSA_(X = Linker 1 + 17aa) ACP203 HSA-X-mIFNa1-X-HSA_(X = Linker 2) ACP204 HSA-X-mIFNa1-X-HSA_(X = Linker 3) ACP205 HSA-X-mIFNa1-X-HSA_(X = Linker 4) ACP206 HSA-X-Human_IFNA2b-X-HSA_(X = Linker 2) ACP207 HSA-X-Human_IFNA2b-X-HSA_(X = Linker 3) ACP208 HSA-X-Human_IFNA2b-X-HSA_(X = Linker 4) ACP211 HSA-X-mouse-IFNg-X-IFNa-X-mouse-IFNg-X-HSA_(X = Linker 1) ACP213 mAlb(D3)-X-mouse-IFNg-X-mAlb(D3)-X-mouse-IFNg-X-mAlb(D3)_(X = Linker 1) ACP214 mAlb(D1-L-D3)-X-mouse-IFNg-X-mAlb(D1-L-D3)-X-mouse-IFNg-X-mAlb(D1-L- D3)_(X = Linker 1) ACP215 HSA-X-mouse-IFNg-X-HSA-X-mouse-IFNg-X-HSA_(X = Linker 1 + 17aa) ACP240 HSA-L-human_p40-L-mouse_p35-LL-Blocker_(non-cleavable; Blocker = Vl/Vh) ACP241 mAlb-X-human_p40-L-mouse_p35-XL-Blocker_(X = Linker 1; Blocker = Vl/Vh) ACP242 human_p40-L-mouse_p35-XL-Blocker-X-mAlb_(X = Linker 1; Blocker = Vl/Vh) ACP243 mIgG1_Fc-X-human_p40-L-mouse_p35-XL-Blocker_(X = Linker 1; Blocker = Vl/Vh) ACP244 human_p40-L-mouse_p35-XL-Blocker-X-mIgG1_Fc_(X = Linker 1; Blocker = Vl/Vh) ACP245 HSA-X-human_p40-L-mouse_p35-XL-Blocker(cleavable)_(X = Linker 1; Blocker = Vl-X-Vh) ACP247 HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = 3CYT5; X = Linker 1) ACP284 HSA-X-mouse_p35-XL-Blocker_(Blocker = Vl/Vh; X = Linker 1) ACP285 HSA-X-human_p40_C199S-L-mouse_p35_C92S-XL-Blocker_(Blocker = _Vl/Vh; X = Linker 1) ACP286 HSA-X-human p40-L(4xG4S (SEQ ID NO: 453))-mouse p35-XL-Blocker_(Blocker = Vl/Vh; X = Linker 1) ACP287 HSA-X-human_p40_mouse_p35-XL-Blocker_(Blocker = Vl/Vh_VH44- VL100 disulfide; X = Linker 1) ACP288 HSA-X-human_p40_mouse_p35-XL-Blocker_(Blocker = Vl/Vh_VH105- VL43_disulfide; X = Linker 1) ACP289 Geneart_WW0048_IL2-X-HSA-LX-blocker_Fusion_protein-6xHis (WW0233) ACP290 IL2-X-HSA-LX-blocker_(X = Linker 1; Blocker = 3TOW69) (WW0234) ACP291 IL2-X-HSA-LX-blocker_(X = Linker 1; Blocker = 3TOW85) (WW0235) ACP292 IL2-X-HSA-LX-blocker_(X = Linker 1; Blocker = 2TOW91) (WW0236) ACP296 IL2-X-HSA-LX-blocker(cleavable)_(X = Linker 1; Blocker = Vh-X-Vl) (WW0250) ACP297 IL2-X-HSA-LX-blocker(A46L)_(X = Linker 1; Blocker = Vh/Vl) (WW0251) ACP298 IL2-X-HSA-LX-blocker(A46G)_(X = Linker 1; Blocker = Vh/Vl) (WW0252) ACP299 IL2(Cys145Ser)-X-HSA-LX-blocker_(X = Linker 1; Blocker = Vh/Vl) (WW0253) ACP300 IL2-X-hAlb-LX-blocker_(X = Linker 1; Blocker = Vh/Vl) (WW0255) ACP302 IL2-X-mAlb-LX-blocker_(X = Linker 1; Blocker = Vh/Vl) (WW0296) ACP303 mAlb-X-IL2(Nterm-41)-X-mALB_(X = Linker 1) ACP304 IL2-X-HSA-LX-blocker-XL-CD25ecd_(X = Linker 1; Blocker = Vh/Vl) (WW0302) ACP305 CD25ecd-LX-IL2-X-HSA-LX-blocker_(X = Linker 1; Blocker = Vh/Vl) (WW0303) ACP306 IL2-XL-CD25ecd-X-HSA-LX-blocker_(X = Linker 1; Blocker = Vh/Vl) (WW0304) ACP309 IL2-X-HSA-LX-blocker(A46S)_(X = Linker 1; Blocker = Vh/Vl) (WW0307) ACP310 IL2-X-HSA-LX-blocker(QAPRL_FR2)_(X = Linker 1; Blocker = Vh/Vl) (WW0308) ACP311 IL2-X-IgG4_Fc(S228P)-LX-Blocker_(X = Linker 1; Blocker = Vh/Vl) (WW0316) ACP312 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(X = Linker 1; Blocker = Vh/Vl) (WW0317) ACP313 IL2-XL-Blocker-X-IgG4_Fc(S228P)_(X = Linker 1; Blocker = Vh/Vl) (WW0318) ACP314 mIgG1_Fc-X-IL2-LX-Blocker_(X = Linker 1; Blocker = Vh/Vl) (WW0354) ACP336 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh-X-Vl_A46S; X = Linker 2) (WW0414) ACP337 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S; X = Linker 2) (WW0415) ACP338 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh-X-Vl; X = Linker 2) (WW0416) ACP339 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl; X = Linker 2) (WW0417) ACP340 IL2-X-anti-HSA-LX-blocker_(Blocker = Hu2TOW91_B; X = Linker 2) (WW0418) ACP341 IL2-X-anti-HSA-LX-blocker_(Blocker = Hu3TOW85_A; X = Linker 2) (WW0419) ACP342 CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh-X- (WW0420) Vl_A46S; X = Linker 2) ACP343 CD25ecd_C213S-LX-IL2-X-anti-HSA-LX- (WW0421) blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S; X = Linker 2) ACP344 CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh-X- (WW0422) Vl; X = Linker 2) ACP345 CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl; X = (WW0423) Linker 2) ACP346 CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker = Hu2TOW91_B; X = Linker 2) (WW0424) ACP347 CD25ecd_C213S-LX-IL2-X-anti-HSA-LX-blocker_(Blocker = Hu3TOW85_A; X = Linker 2) (WW0425) ACP348 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh-X-Vl_A46S; X = (WW0426) Linker 2) ACP349 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh\Vl_A46S; X = Linker (WW0427) 2) ACP350 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.F03_Vh-X-Vl; X = Linker 2) (WW0428) ACP351 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.F03_Vh\Vl; X = Linker 2) (WW0429) ACP352 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = Hu2TOW91_B; X = Linker 2) (WW0430) ACP353 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = Hu3TOW85_A; X = Linker 2) (WW0431) ACP354 IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh- (WW0432) X-Vl_A46S; X = Linker 2) ACP355 IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX- (WW0433) Blocker_(Blocker = VHVL.F2.high.A02_Vh\Vl_A46S; X = Linker 2) ACP356 IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker = VHVL.F2.high.F03_Vh- (WW0434) X-Vl; X = Linker 2) ACP357 IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX- (WW0435) Blocker_(Blocker = VHVL.F2.high.F03_Vh\Vl; X = Linker 2) ACP358 IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker = Hu2TOW91_B; X = (WW0436) Linker 2) ACP359 IgG4_Fc(S228P)-X-CD25ecd_C213S-LX-IL2-LX-Blocker_(Blocker = Hu3TOW85_A; X = (WW0437) Linker 2) ACP371 IL2-X-anti-HSA-LX-blocker_(Blocker = Vh/Vl_VH44-VL100_disulfide; X = Linker 2) (WW0513) ACP372 IL2-X-anti-HSA-LX-blocker_(Blocker = Vh/Vl_VH105-VL43_disulfide; X = Linker 2) (WW0514) ACP373 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_VH44- (WW0515) VL100_disulfide; X = Linker 2) ACP374 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_VH105- (WW0516) VL43_disulfide; X = Linker 2) ACP375 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH44- (WW0517) VL100_disulfide; X = Linker 2) ACP376 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH105-VL43_disulfide X = (WW0521) Linker 2) ACP377 IL2-X-anti-HSA-LX-blocker_(Blocker = Hu2TOW91_A; X = Linker 2) (WW0519) ACP378 IL2-X-anti-HSA-LX-Heavy_blocker_Fab_(Blocker = VH-CH1; X = Linker 2) (WW0520) ACP379 IgG4_Fc(S228P)-X-IL2-LX-Heavy_blocker_Fab_(Blocker = VH-CH1; X = Linker 2) (WW0521) ACP383 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = Vh/Vl_VH44-VL100_disulfide; X = LINKER 2) (WW0525) ACP38 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = Vh/Vl_VH105-VL43_disulfide; X = MMP14-1) (WW05264) ACP385 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_VH44- (WW0527) VL100_disulfide; X = LINKER 2) ACP386 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_VH105- (WW0528) VL43_disulfide; X = Linker 2) ACP387 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH44- (WW0529) VL100_disulfide; X = Linker 2) ACP388 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH105- (WW0530) VL43_disulfide; X = Linker 2) ACP389 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = Hu2TOW91_A; X = Linker 2) (WW0531) ACP390 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S_VH44- (WW0532) VL100_disulfide; X = Linker 2) ACP391 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S_VH44- (WW0533) VL100_disulfide; X = Linker 2) ACP392 IL2-XL-CD25ecd_C213S-X-HSA-LX- (WW0534) blocker_(Blocker = VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C; X = Linker 2) ACP393 IL2-XL-CD25ecd_C213S-X-HSA-LX- (WW0535) blocker_(Blocker = VHVL.F2.high.A02_Vh_Q105C_Vl_A43C; X = Linker 2) ACP394 IL2-XL-CD25ecd_C213S-X-HSA-LX- (WW0536) blocker_(Blocker = VHVL.F2.high.F03_Vh_G44C_Vl_G100C; X = Linker 2) ACP395 IL2-XL-CD25ecd_C213S-X-HSA-LX- (WW0537) blocker_(Blocker = VHVL.F2.high.F03_Vh_Q105C_Vl_A43C; X = Linker 2) ACP396 IL2-XL-CD25ecd_C213S-X-HSA-LX-blocker_(Blocker = Hu2TOW91_A; X = Linker 2) (WW0538) ACP397 IL2-XL-CD25ecd_C213S-X-HSA-LX-blocker_(Blocker = Hu2TOW91_B; X = Linker 2) (WW0539) ACP398 IL2-XL-CD25ecd_C213S-X-HSA-LX-Heavy_blocker_Fab_(Blocker = VH-CH1; X = Linker 2) (WW0540) ACP399 Blocker-XL-HSA-X-IL2(Nterm-41)-X- HSA_(Blocker = VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C; X = Linker 2) ACP400 Blocker-XL-HSA-X-IL2(Nterm-41)-X- HSA_(Blocker = VHVL.F2.high.A02_Vh_Q105C_Vl_A43C; X = Linker 2) ACP401 Blocker-XL-HSA-X-IL2(Nterm-41)-X- HSA_(Blocker = VHVL.F2.high.F03_Vh_G44C_Vl_G100C; X = Linker 2) ACP402 Blocker-XL-HSA-X-IL2(Nterm-41)-X- HSA_(Blocker = VHVL.F2.high.F03_Vh_Q105C_Vl_A43C; X = Linker 2) ACP403 Blocker-XL-HSA-X-IL2(Nterm-41)-X-HSA_(Blocker = Hu2TOW91_A; X = Linker 2) ACP404 Blocker-XL-HSA-X-IL2(Nterm-41)-X-HSA_(Blocker = Hu2TOW91_B; X = Linker 2) ACP405 Heavy_Blocker_Fab-XL-HSA-X-IL2(Ntenn-41)-X-HSA_(Blocker = VH-CH1; X = Linker 2) ACP406 mIgG1_Fc(S228P)-X-IL2-LX-Heavy_blocker_Fab_(Blocker = VH-CH1; X = Linker 2) (WW0548) ACP407 mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_VH44- (WW0549) VL100_disulfide; X = Linker 2) ACP408 mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S_VH44- (WW0550) VL100_disulfide; X = Linker 2) ACP409 mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_VH105- (WW0551) VL43_disulfidel; X = Linker 2) ACP410 mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH44- (WW0552) VL100_disulfidel; X = Linker 2) ACP411 mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH105- (WW0553) VL43_disulfidel; X = Linker 2) ACP412 mIgG1_Fc(S228P)-X-IL2-LX-blocker_(Blocker = Hu2TOW91_A; X = Linker 2) (WW0554) ACP413 CD25_213S-L-Kappa_blocker_Fab_(Blocker = VHVL.F2.high.A02_A46S_Kappa) (WW0555) ACP414 CD25_213S-L-Kappa_blocker_Fab_(Blocker = VHVL.F2.high.F03_Kappa) (WW0556) ACP415 IL2-XL-blocker-L-CD25_213S-X- (WW0557) HSA_Blocker = VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C; X = Linker 2) ACP416 IL2-XL-blocker-L-CD25_213S-X- (WW0558) HSA_(Blocker = VHVL.F2.high.A02_Vh_Q105C_Vl_A43C; X = Linker 2) ACP417 IL2-XL-blocker-L-CD25_213S-X- (WW0559) HSA_(Blocker = VHVL.F2.high.F03_Vh_G44C_Vl_G100C; X = Linker 2) ACP418 IL2-XL-blocker-L-CD25_213S-X- (WW0560) HSA_(Blocker = VHVL.F2.high.F03_Vh_Q105C_Vl_A43C; X = Linker 2) ACP419 IL2-XL-blocker-L-CD25_213S-X-HSA_(Blocker = Hu2TOW91_A; X = Linker 2) (WW0561) ACP420 IL2-XL-blocker-L-CD25_213S-X-HSA_(Blocker = Hu2TOW91_B; X = Linker 2) (WW0562) ACP421 HSA-X-blocker-L-CD25_213S-LX- (WW0563) IL2_(Blocker = VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C; X = Linker 2) ACP422 HSA-X-blocker-L-CD25_213S-LX- (WW0564) IL2_(Blocker = VHVL.F2.high.A02_Vh_Q105C_Vl_A43C; X = Linker 2) ACP423 HSA-X-blocker-L-CD25_213S-LX- (WW0565) IL2_(Blocker = VHVL.F2.high.F03_Vh_G44C_Vl_G100C; X = Linker 2) ACP424 HSA-X-blocker-L-CD25_213S-LX- (WW0566) IL2_(Blocker = VHVL.F2.high.F03_Vh_Q105C_Vl_A43C; X = Linker 2) ACP425 HSA-X-blocker-L-CD25_213S-LX-IL2_(Blocker = Hu2TOW91_A; X = Linker 2) (WW0567) ACP426 HSA-X-blocker-L-CD25_213S-LX-IL2_(Blocker = Hu2TOW91_B; X = Linker 2) (WW0568) ACP427 IL2-X-anti-HSA-LX-Blocker1-L- (WW0569) Blocker2_(Blocker1 = VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C, Blocker2 = Hu2TOW91_A; X = Linker 2) ACP428 IL2-X-anti-HSA-LX-Blocker1-L- (WW0570) Blocker2_(Blocker1 = VHVL.F2.high.A02_Vh_Q105C_Vl_A43C, Blocker2 = Hu2TOW91_A; X = Linker 2) ACP429 IL2-X-anti-HSA-LX-Blocker1-L- (WW0571) Blocker2_(Blocker1 = VHVL.F2.high.F03_Vh_G44C_Vl_G100C, Blocker2 = Hu2TOW91_A; X = Linker 2) ACP430 IL2-X-anti-HSA-LX-Blocker1-L- (WW0572) Blocker2_(Blocker1 = VHVL.F2.high.F03_Vh_Q105C_Vl_A43C, Blocker2 = Hu2TOW91_A; X = Linker 2) ACP431 IL2-X-anti-HSA-LX-Blocker1-L- (WW0573) Blocker2_(Blocker1 = VHVL.F2.high.A02_Vh_G44C_Vl_A46S_G100C, Blocker2 = Hu2TOW91_B; X = Linker 2) ACP432 IL2-X-anti-HSA-LX-Blocker1-L- (WW0574) Blocker2_(Blocker1 = VHVL.F2.high.A02_Vh_Q105C_Vl_A43C, Blocker2 = Hu2TOW91_B; X = Linker 2) ACP433 IL2-X-anti-HSA-LX-Blocker1-L- (WW0575) Blocker2_(Blocker1 = VHVL.F2.high.F03_Vh_G44C_Vl_G100C, Blocker2 = Hu2TOW91_B; X = Linker 2) ACP434 IL2-X-anti-HSA-LX-Blocker1-L- (WW0576) Blocker2_(Blocker1 = VHVL.F2.high.F03_Vh_Q105C_Vl_A43C, Blocker2 = Hu2TOW91_B; X = Linker 2) ACP439 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.C07_Vh/Vl; X = Linker 2) (WW0581) ACP440 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.C07_Vh/Vl_A46S; X = Linker 2) (WW0582) ACP441 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.C07_Vh/Vl_A46L; X = Linker 2) (WW0583) ACP442 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.C07_Vh/Vl_A46S_VH44- (WW0584) VL100_disulfide; X = Linker 2) ACP443 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.C07_Vh/Vl_A46L_VH44- (WW0585) VL100_disulfide; X = Linker 2) ACP444 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.C07_Vh/Vl_VH105- (WW0586) VL43_disulfide; X = Linker 2) ACP445 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh-X-Vl_A46L; X = Linker 2) (WW0587) ACP446 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46L; X = Linker 2) (WW0588) ACP447 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46L_VH44- (WW0589) VL100_disulfide; X = Linker 2) ACP451 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S; X = Linker 3) (WW0615) ACP452 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl; X = Linker 3) (WW0616) ACP453 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S_VH44- (WW0617) VL100_disulfide; X = Linker 3) ACP454 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_VH105- (WW0618) VL43_disulfidel; X = Linker 3) ACP455 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH44- (WW0619) VL100_disulfide; X = Linker 3) ACP456 IL2-X-anti-HSA-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH105- (WW0620) VL43_disulfideX = Linker 3) ACP457 IL2-X-anti-HSA-LX-Heavy_blocker_Fab_(Blocker = VH-CH1; X = Linker 3) (WW0621) ACP458 IgG4_Fc(S228P)-X-IL2-LX-Heavy_blocker_Fab_(Blocker = VH-CH1; X = Linker 3) (WW0622) ACP459 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh\Vl_A46S; X = Linker 3) (WW0623) ACP460 IgG4_Fc(S228P)-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.F03_Vh\Vl; X = Linker 3) (WW0624) ACP461 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S_VH44- (WW0625) VL100_disulfide; X = Linker 3) ACP462 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_VH105- (WW0626) VL43_disulfidel; X = Linker 3) ACP463 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH44- (WW0627) VL100_disulfidel; X = Linker 3) ACP464 IgG4_Fc(S228P)-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH105- (WW0628) VL43_disulfidel; X = Linker 3) ACP465 mIgG1_Fc-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh\Vl_A46S; X = Linker 3) (WW0629) ACP466 mIgG1_Fc-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.F03_Vh\Vl; X = Linker 3) (WW0630) ACP467 mIgG1_Fc-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_A46S_VH44- (WW0631) VL100_disulfide; X = Linker 3) ACP468 mIgG1_Fc-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.A02_Vh/Vl_VH105- (WW0632) VL43_disulfidel; X = Linker 3) ACP469 mIgG1_Fc-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH44- (WW0633) VL100_disulfidel; X = Linker 3) ACP470 mIgG1_Fc-X-IL2-LX-blocker_(Blocker = VHVL.F2.high.F03_Vh/Vl_VH105- (WW0634) VL43_disulfidel; X = Linker 3) ACP471 mIgG1_Fc-X-IL2-LX-Heavy_blocker_Fab_(Blocker = VH-CH1; X = Linker 3) (WW0642) WW0301 IL2-X-anti-HSA-LL-blocker_(X = Linker1_Blocker = Vh-Vl) WW0353 IL2-X-mIgG1_Fc-LX-Blocker_(X = Linker1_Blocker = Vh-Vl) WW0355 IL2-XL-Blocker-X-mIgG1_Fc_(X = Linker1_Blocker = Vh-Vl) WW0365 IL-2-L-anti-HSA-LX-Blocker_(instead_of_WW0048_IL2-X-anti-HSA-LX- blocker)_(X = Linker1) WW0366 IL-2-X-anti-HSA_(GeneArt_version_of_WW0061)_(X = Linker1) WW0472 mIgG1_Fc-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh-X-Vl_A46S_X = Linker2) WW0473 mIgG1_Fc-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.A02_Vh-Vl_A46S_X = Linker2) WW0474 mIgG1_Fc-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.F03_Vh-X-Vl_X = Linker2) WW0475 mIgG1_Fc-X-IL2-LX-Blocker_(Blocker = VHVL.F2.high.F03_Vh-Vl_X = Linker2) WW0476 mIgG1_Fc-X-IL2-LX-Blocker_(Blocker = Hu2TOW91_B_X = Linker2) WW0477 mIgG1_Fc-X-IL2-LX-Blocker_(Blocker = Hu3TOW85_A_X = Linker2) WW0641 anti-HSA-X-human_p40_mouse_p35-XL-Blocker_(Blocker = Vl/Vh_VH105- VL43_disulfide; X = Linker1) WW0649 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Vl/Vh_X = Linker2) WW0650 anti-HSA-X-human_p40-L-Human_p35-XL-Blocker_(Blocker = Vl/Vh_X = Linker2) WW0651 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Vl/Vh_X = Linker3) WW0652 anti-HSA-X-human_p40-L-Human_p35-XL-Blocker_(Blocker = Vl/Vh_X = Linker3) WW0662 anti-HSA-X-human_p40-L-mouse_p35-XL- Blocker_(Blocker = Opt1_Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0663 anti-HSA-X-human_p40-L-human_p35-XL- Blocker_(Blocker = Opt1_Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0664 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt2_Lv_N31E- Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0665 anti-HSA-X-human_p40-L-human_p35-XL-Blocker_(Blocker = Opt2_Lv_N31E- Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0666 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt3_LV_S30D- Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0667 anti-HSA-X-human_p40-L-human_p35-XL-Blocker_(Blocker = Opt3_LV_S30D- Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0668 anti-HSA-X-human_p40-L-mouse_p35-XL- Blocker_(Blocker = Opt4_LV_S30D_N31E_Vl/Vh_X = Linker2) WW0669 anti-HSA-X-human_p40-L-human_p35-XL- Blocker_(Blocker = Opt4_LV_S30D_N31E_Vl/Vh_X = Linker2) WW0670 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt5_Lv_S30D_N31E- Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0672 anti-HSA-X-human_p40-L-mouse_p35-XL- Blocker_(Blocker = Opt6_Lv_R27E_T32D(LCharge_16(combo2))_Vl/Vh_X = Linker2) WW0673 anti-HSA-X-human_p40-L-human_p35-XL- Blocker_(Blocker = Opt6_Lv_R27E_T32D(LCharge_16(combo2))_Vl/Vh_X = Linker2) WW0674 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt7_Lv_S30E- Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0675 anti-HSA-X-human_p40-L-human_p35-XL-Blocker_(Blocker = Opt7_Lv_S30E- Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0676 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt8_Lv_S30E N31E_Vl/Vh_X = Linker2) WW0677 anti-HSA-X-human_p40-L-human_p35-XL-Blocker_(Blocker = Opt8_Lv_S30E N31E_Vl/Vh_X = Linker2) WW0678 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt9_Lv_N31E- Hv_D53E_Vl/Vh_X = Linker2) WW0679 anti-HSA-X-human_p40-L-human_p35-XL-Blocker_(Blocker = Opt9_Lv_N31E- Hv_D53E_Vl/Vh_X = Linker2) WW0680 anti-HSA-X-human_p40-L-mouse_p35-XL- Blocker_(Blocker = Opt1_Hv_D53E_D61E_Vl/Vh_X = Linker3 WW0681 anti-HSA-X-human_p40-L-human_p35-XL- Blocker_(Blocker = Opt1_Hv_D53E_D61E_Vl/Vh_X = Linker3) WW0682 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt2_Lv_N31E- Hv_D53E_D61E_Vl/Vh_X = Linker3 WW0683 anti-HSA-X-human_p40-L-human_p35-XL-Blocker_(Blocker = Opt2_Lv_N31E- Hv_D53E_D61E_Vl/Vh_X = Linker3) WW0684 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt3_LV_S30D- Hv_D53E_D61E_Vl/Vh_X = Linker3 WW0685 anti-HSA-X-human_p40-L-human_p35-XL-Blocker_(Blocker = Opt3_LV_S30D- Hv_D53E_D61E_Vl/Vh_X = Linker3) WW0686 anti-HSA-X-human_p40-L-mouse_p35-XL- Blocker_(Blocker = Opt4_LV_S30D_N31E_Vl/Vh_X = Linker3 WW0687 anti-HSA-X-human_p40-L-human_p35-XL- Blocker_(Blocker = Opt4_LV_S30D_N31E_Vl/Vh_X = Linker3) WW0688 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt5_Lv_S30D_N31E- Hv_D53E_D61E_Vl/Vh_X = Linker3 WW0689 anti-HSA-X-human_p40-L-human_p35-XL-Blocker_(Blocker = Opt5_Lv_S30D_N31E- Hv_D53E_D61E_Vl/Vh_X = Linker3) WW0690 anti-HSA-X-human_p40-L-mouse_p35-XL- Blocker_(Blocker = Opt6_Lv_R27E_T32D(LCharge_16(combo2))_Vl/Vh_X = Linker3 WW0691 anti-HSA-X-human_p40-L-human_p35-XL- Blocker_(Blocker = Opt6_Lv_R27E_T32D(LCharge_16(combo2))_Vl/Vh_X = Linker3) WW0692 anti-HSA-X-human_p40-L-mouse_p35-XL-Blocker_(Blocker = Opt7_Lv_S30E- Hv_D53E_D61E_Vl/Vh_X = Linker3 WW0693 anti-HSA-X-human_p40-L-human_p35-XL-Blocker_(Blocker = Opt7_Lv_S30E- Hv_D53E_D61E_Vl/Vh_X = Linker3) WW0694 anti-HSA-X-human_p40-L-mouse_p35-XL- Blocker_(Blocker = Opt8_Lv_S30E_N31E_Vl/Vh_X = Linker3 WW0695 anti-HSA-X-human_p40-L-human_p35-XL- Blocker_(Blocker = Opt8_Lv_S30E_N31E_Vl/Vh_X = Linker3) WW0698 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_IGLC2-01_X = Linker2) WW0699 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_IGLC2-01_X = Linker2) WW0700 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_N31E_IGLC2-01_X = Linker2) WW0701 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_N31E_IGLC2-01_X = Linker2) WW0702 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_IGLC2-01_X = Linker2) WW0703 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_IGLC2-01_X = Linker2) WW0704 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_N31E_IGLC2-01_X = Linker2) WW0705 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_N31E_IGLC2-01_X = Linker2) WW0706 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_R27E_T32D_IGLC2-01_X = Linker2) WW0707 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_R27E_T32D_IGLC2-01_X = Linker2) WW0708 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30E_IGLC2-01_X = Linker2) WW0709 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30E_IGLC2-01_X = Linker2) WW0710 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30E_N31E_IGLC2-01_X = Linker2) WW0711 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30E_N31E_IGLC2-01_X = Linker2) WW0712 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_IGLC2-01_X = Linker3) WW0713 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_IGLC2-01_X = Linker3) WW0714 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_N31E_IGLC2-01_X = Linker3) WW0715 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_N31E_IGLC2-01_X = Linker3) WW0716 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_IGLC2-01_X = Linker3) WW0717 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_IGLC2-01_X = Linker3) WW0718 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_N31E_IGLC2-01_X = Linker3) WW0719 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_N31E_IGLC2-01_X = Linker3) WW0720 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_R27E_T32D_IGLC2-01_X = Linker3) WW0721 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_R27E_T32D_IGLC2-01_X = Linker3) WW0722 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30E_IGLC2-01_X = Linker3) WW0723 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30E_IGLC2-01_X = Linker3) WW0724 anti-HSA-X-human_p40-L-mouse_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30E_N31E_IGLC2-01_X = Linker3) WW0725 anti-HSA-X-human_p40-L-human_p35-XL- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30E_N31E_IGLC2-01_X = Linker3) WW0726 Fab_Heavy_Blocker_(Blocker = IL-12_Heavy_Fab_IgG1_Fab) WW0727 Fab_Heavy_Blocker_(Blocker = IL-12_Heavy_Fab_D53E_D61E_IgG1_Fab) WW0728 Fab_Heavy_Blocker_(Blocker = IL-12_Heavy_Fab_D53E_IgG1_Fab) WW0765 human_p40-L-mouse_p35-X-anti-HSA-L- Blocker_(Blocker = Opt1_Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0766 human_p40-L-human_p35-X-anti-HSA-L- Blocker_(Blocker = Opt1_Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0767 human_p40-L-mouse_p35-X-anti-HSA-L-Blocker_(Blocker = Opt5_Lv_S30D_N31E- Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0768 human_p40-L-human_p35-X-anti-HSA-L-Blocker_(Blocker = Opt5_Lv_S30D_N31E- Hv_D53E_D61E_Vl/Vh_X = Linker2) WW0769 human_p40-L-mouse_p35-X-anti-HSA-L- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_IGLC2-01_X = Linker2) WW0770 human_p40-L-human_p35-X-anti-HSA-L- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_IGLC2-01_X = Linker2) WW0771 human_p40-L-mouse_p35-X-anti-HSA-L- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_N31E_IGLC2-01_X = Linker2) WW0772 human_p40-L-human_p35-X-anti-HSA-L- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_N31E_IGLC2-01_X = Linker2) WW0796 human_p40-L-mouse_p35-X-anti-HSA-L-Blocker_(Blocker = Opt1_Hv_D53E_D61E_Vl- Vh_X = Linker3) WW0797 human_p40-L-human_p35-X-anti-HSA-L-Blocker_(Blocker = Opt1_Hv_D53E_D61E_Vl- Vh_X = Linker3) WW0798 human_p40-L-mouse_p35-X-anti-HSA-L-Blocker_(Blocker = Opt5_Lv_S30D_N31E- Hv_D53E_D61E_Vl-Vh_X = Linker3) WW0799 human_p40-L-human_p35-X-anti-HSA-L-Blocker_(Blocker = Opt5_Lv_S30D_N31E- Hv_D53E_D61E_Vl-Vh_X = Linker3) WW0800 human_p40-L-mouse_p35-X-anti-HSA-L- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_IGLC2-01_X = Linker3) WW0801 human_p40-L-human_p35-X-anti-HSA-L- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_IGLC2-01_X = Linker3) WW0802 human_p40-L-mouse_p35-X-anti-HSA-L- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_N31E_IGLC2-01_X = Linker3) WW0803 human_p40-L-human_p35-X-anti-HSA-L- Fab_Lambda_Blocker_(Blocker = Lambda_Fab_S30D_N31E_IGLC2-01_X = Linker3) WW0643 HSA-X-mIFNa11-X-HSA_(X = Linker2) WW0644 HSA-X-mIFNa11-X-HSA_(X = Linker3) WW0645 HSA-X-Human_IFNA14-X-HSA_(X = Linker2) WW0646 HSA-X-Human_IFNA14-X-HSA_(X = Linker3) WW0647 Mouse_IFNA11 WW0648 Human_IFNA14 WW0781 HSA-X-Human_IFNA2b_T129E-X-HSA_(X = Linker2) WW0782 HSA-X-Human_IFNA14_N95D-X-HSA_(X = Linker2) WW0783 HSA-X-Human_IFNA14_N25D_S27P_N95D-X-HSA_(X = Linker2) WW0784 Human_IFNA2b_T129E WW0785 Human_IFNA14_N95D WW0786 Human_IFNA14_N25D_S27P_N95D WW0815 mAlb-X-mIFNa1-X-mAlb_(X = Linker3) WW0816 mAlb-X-mIFNa11-X-mAlb_(X = Linker3) WW0817 anti-HSA-X-mIFNa1-X-mAlb_(X = Linker3) WW0818 anti-HSA-X-mIFNa11-mAlb_(X = Linker3) WW0819 mAlb-X-mIFNa1-X-anti-HSA_(X = Linker3) WW0820 mAlb-X-mIFNa11-anti-HSA_(X = Linker3) WW0821 Alb-X-Human_IFNA2b-X-Alb_(X = Linker3) WW0822 Alb-X-Human_IFNA14-X-Alb_(X = Linker3) WW0831 Alb-X-IFNa8-X-Alb_(X = Linker3) WW0832 Alb-X-IFNa16-Alb_(X = Linker3) WW0833 Anti-HSA-X-IFNa8-X-anti-HSA_(X = Linker3) WW0834 Anti-HSA-X-IFNa16-X-anti-HSA_(X = Linker3) WW0737 HSA-X-mIFNb-X-HSA_(X = Linker2) WW0738 HSA-X-mIFNb-X-HSA_(X = Linker3) WW0739 HSA-X-mIFNb_C38S-X-HSA_(X = Linker2) WW0740 HSA-X-mIFNb_C38S-X-HSA_(X = Linker3) WW0741 HSA-X-Human_IFNB-X-HSA_(X = Linker2) WW0742 HSA-X-Human_IFNB-X-HSA_(X = Linker3) WW0743 HSA-X-Human_IFNB_C38S-X-HSA_(X = Linker2) WW0744 HSA-X-Human_IFNB_C38S-X-HSA_(X = Linker3) WW0745 Mouse_IFNb WW0746 Mouse_IFNb_C38S WW0747 Human_IFNB WW0748 Human_IFNAB_C38S WW0787 HSA-X-Human_IFNB_N101Q-X-HSA_(X = Linker2) WW0788 HSA-X-Human_IFNB_N101Q_C38S-X-HSA_(X = Linker2) WW0789 Human_IFNB_N101Q WW0790 Human_IFNB_C38S_N101Q WW0729 IL2-L-anti-HSA-LL-Heavy_blocker_Fab_(Blocker = VH-CH1_non-cleavable) WW0734 IL2-X-anti-HSA-LL-Heavy_blocker_Fab_(Blocker = VH-CH1_X = Linker1) WW0735 IL2-X-anti-HSA-LL-Heavy_blocker_Fab_(Blocker = VH-CH1_X = Linker2) WW0736 IL2-X-anti-HSA-LL-Heavy_blocker_Fab_(Blocker = VH-CH1_X = Linker3) WW0792 Anti-IL-2_Fab_Heavy_IgG1_Blocker_His_tag WW0061 IL2-X-anti-HSA_Fusion_(X = Linker1) ACP293 3TOW69sdAb (WW0237) ACP294 3TOW85sdAb (WW0238) ACP295 2TOW91sdAb (WW0239) ACP315 Hu2TOW91_A (WW0368) ACP316 Hu2TOW91_B (WW0369) ACP317 Hu2TOW91_C (WW0370) ACP318 Hu2TOW91_D (WW0371) ACP319 HE_LM_2TOW91 (WW0372) ACP320 HE_L_2TOW91 (WW0373) ACP321 Hu3TOW85_A (WW0374) ACP322 Hu3TOW85_B (WW0375) ACP323 Hu3TOW85_C (WW0376) ACP324 Hu3TOW85_D (WW0377) ACP325 HE_LM_3TOW85 (WW0378) ACP326 HE_L_3TOW85 (WW0379) ACP327 HE_LM_R45L_3TOW85 (WW0380) ACP328 Hu3TOW69_A (WW0381) ACP329 Hu3TOW69_B (WW0382) ACP330 Hu3TOW69_C (WW0383) ACP331 Hu3TOW69_D (WW0384) ACP332 Hu3TOW69_E (WW0385) ACP333 HE_LM_3TOW69 (WW0386) ACP334 HE_L_3TOW69 (WW0387) ACP335 HE_LM_R45L_3TOW69 (WW0388_(—) ACP360 Vh-Vl_3xG4S_A46S (“3xG4S” is disclosed as SEQ ID NO: 452) (WW0438) ACP361 Vh-Vl_3xG4S_A46S (“3xG4S” is disclosed as SEQ ID NO: 452) (WW0439) ACP362 Vh-X-Vl_X = Linker2 (WW0440) ACP363 Vh-X-Vl_X = Linker2_A46S (WW0441) ACP364 VHVL.F2.high.A02_Vh-Vl_3xG4S (“3xG4S” is disclosed as SEQ ID NO: 452) (WW0442) ACP365 VHVL.F2.high.A02_Vh-Vl_3xG4S_A46S (“3xG4S” is disclosed as SEQ ID NO: 452) (WW0443) ACP366 VHVL.F2.high.A02_Vh-X-Vl_X = Linker2 (WW0444) ACP367 VHVL.F2.high.A02_Vh-X-Vl_X = Linker2_A46S (WW0445) ACP368 VHVL.F2.high.F03_Vh-Vl_3xG4S (“3xG4S” is disclosed as SEQ ID NO: 452) (WW0446) ACP369 VHVL.F2.high.F03_Vh-X-Vl_X = Linker2 (WW0449) ACP370 VHVL.F2.high.C07_Vh-Vl_3xG4S (“3xG4S” is disclosed as SEQ ID NO: 452) (WW0450) ACP380 Kappa_blocker_Fab_(Blocker = Kappa) (WW0522) ACP381 Kappa_blocker_Fab_(Blocker = VHVL.F2.high.A02_A46S_Kappa) (WW0523) ACP382 Kappa_blocker_Fab_(Blocker = VHVL.F2.high.F03_Kappa) (WW0524) ACP434 IL2-X-anti-HSA-LX-Blocker1-L- (WW0576) Blocker2_(Blocker1 = VHVL.F2.high.F03_Vh_Q105C_Vl_A43C_Blocker2 = Hu2TOW91_B_X = Linker2) ACP435 Kappa_blocker1_Fab-L- (WW0577) blocker2_(Blocker1 = VHVL.F2.high.A02_A46S_Kappa_Blocker2 = Hu2TOW91_A) ACP436 Kappa_blocker1_Fab-L- (WW0578) blocker2_(Blocker1 = VHVL.F2.high.A02_A46S_Kappa_Blocker2 = Hu2TOW91_B) ACP437 Kappa_blocker1_Fab-L- (WW0579) blocked_(Blocker1 = VHVL.F2.high.F03_Kappa_Blocker2 = Hu2TOW91_A) ACP438 Kappa_blocker1_Fab-L- (WW0580) blocker2_(Blocker1 = VHVL.F2.high.F03_Kappa_Blocker2 = Hu2TOW91_B) ACP448 Kappa_blocker_Fab_(Blocker = VHVL.F2.high.C07_A46S_Kappa) (WW0590) ACP449 Kappa_blocker_Fab_(Blocker = VHVL.F2.high.C07_A46L_Kappa) (WW0591) ACP450 Kappa_blocker_Fab_(Blocker = VHVL.F2.high.A02_A46L_Kappa) (WW0592)

Sequence table SEQ ID NO. Name Sequence 1 Human IL-2 MYRMQLLSCI ALSLALVTNS APTSSSTKKT QLQLEHLLLD LQMILNGINN YKNPKLTRML TFKFYMPKKA TELKHLQCLE EELKPLEEVL NLAQSKNFHL RPRDLISNIN VIVLELKGSE TTFMCEYADE TATIVEFLNR WITFCQSIISTLT 2 Human MKWVTFISLL FLFSSAYSRG VFRRDAHKSE VAHRFKDLGE ENFKALVLIA serum FAQYLQQCPF EDHVKLVNEV TEFAKTCVAD ESAENCDKSL HTLFGDKLCT albumin VATLRETYGE MADCCAKQEP ERNECFLQHK DDNPNLPRLV RPEVDVMCTA FHDNEETFLK KYLYEIARRH PYFYAPELLF FAKRYKAAFT ECCQAADKAA CLLPKLDELR DEGKASSAKQ GLKCASLQKF GERAFKAWAV ARLSQRFPKA EFAEVSKLVT DLTKVHTECC HGDLLECADD RADLAKYICE NQDSISSKLK ECCEKPLLEK SHCIAEVEND EMPADLPSLA ADFVGSKDVC KNYAEAKDVF LGMFLYEYAR RHPDYSVVLL LRLAKTYETT LEKCCAAADP HECYAKVFDE FKPLVEEPQN LIKQNCELFE QLGEYKFQNA LLVRYTKKVP QVSTPTLVEV SRNLGKVGSK CCKHPEAKRM PCAEDCLSVF LNQLCVLHEK TPVSDRVTKC CTESLVNGRPCFSALEVDETYVPKEFNAETFTFHADICTL SEKERQIKKQTALV ELVKHK PKATKEQLKAVMDDFAAFVEKCCKADDKET CFAEEGKKLVAASQAALGL 45 ACP12 QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITR (IL2 fusion GGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYW protein) GKGTQVTVSSggggsggggsggggsaptsssticktqlqlehllldlqmilnginnyknpkltrmlfficfympkk atellchlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetative flnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ APGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTA VYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsEVQLVESGGGLVQPGGSLR LSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRD NAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGS GGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGK APKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYT FGGGTKVEIKHHHHHH 46 ACP13 QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITR (IL2 fusion GGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYW protein) GKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFR YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKgg ggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGK GLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYC TIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSaptsssticktqlqlehllldlqmilnginny knpkltrmlfficfympkkatellchlqcleeelkpleevinlaqsknfblrprdlisninvivlelk gsettfmceyadetativeflnrwitfcqsiistltHHHHHH 47 ACP14 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (IL2 fusion SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL protein) DYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCK ASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSL WW0045QPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsSG GPGPAGMKGLPGSaptsssticktqlqlehllldlqmilnginnyknpkltrmifficfympkkatelkhlqcleee lkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGM KGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLE WVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIG GSLSVSSQGTLVTVSSHHHHHH 48 ACP15 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (IL2 fusion SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL protein) DYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCK (WW0047) ASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsEV QLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS GRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQ GTLVTVSSggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginn yknpkltrinlifkfympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetat iveflnrwitfcqsiistltHHHHHH 49 ACP16 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (IL2 fusion dlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVES protein) GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL (WW0048) YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLV QPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWY QQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YYTYPYTFGGGTKVEIKHHHHHH 50 ACP17 QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITR (IL2 fusion GGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYW protein) GKGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkltrmilfklympkk atelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfc qsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ APGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTA VYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAG MKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGL EWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR DSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVG DRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 51 ACP18 QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITR (IL2 fusion GGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYW protein) GKGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkltrmilfklympkk atelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitf cqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ APGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTA VYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsEVQLVESG GGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPD TVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTT VTVSSsggpgpagmkglpgsDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWY QQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YYTYPYTFGGGTKVEIKHHHHHH 52 ACP19 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevi (IL2 fusion nlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein) MKGLPGSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVR QAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTA VYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggg gsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSI SGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSV SSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSID IMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSL KPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHH** 53 ACP20 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleev (IL2 fusion dinlaqsknfhlrprlisninvivlelkgsetifmceyadetativeflnrwitfcqsiistltSGGPGPA protein) GGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSP (WW0056) GMKGLPGSEVQLVESDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGT TVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTN VGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCQQYYTYPYTFGGGTKVEIKHHHHHH 54 ACP21 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggs (IL2 fusion ggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVR protein) QAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTA (WW0057) VYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 55 ACP22 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (IL2 fusion dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggs protein) ggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVR QAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTA VYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGM KGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLE WVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIG GSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASG RIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYL QMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHH 56 ACP23 QVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIIN (IL2 fusion SVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIY protein) WGQGTQVTVSSSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASG FTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYS ASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQ PGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKG LPGSaptssstldctqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkple evinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 57 ACP24 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (IL2 fusion SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL protein) DYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCK (WW0074) ASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSaptssstIcktqlql ehllldlqmilnginnyknpkltrmlfficfympldcatelkittqcleeelkpleevinlaqsknf ittrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 58 ACP25 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (IL2 fusion SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL protein) DYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCK (WW0075) ASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsSG GPGPAGMKGLPGSaptssstIcktqlqlehllldlqmilnginnyknpkftrmltfkfympkkatelkhlqcleee lkpleevinlaqsknflilmrdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 59 ACP26 QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITR (IL2 fusion GGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYW protein) GKGTQVTVSSggggsggggsggggsaptssstIcktqlqlehllldlqmilnginnyknpkltrmltficfympkk atelkittqcleeelkpleevinlaqsknfittrprdlisninvivlelkgsettfmceyadetativeflnrwi tfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ APGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTA VYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsQVQLQQSGAELVRPGT SVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKFKGKA TLTADKSSSTAYMQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTV SSggggsggggsggggsDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWY QQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQ SNEDPYTFGGGTKLEIKHHHHHHEPEA 60 ACP27 QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITR (IL2 fusion GGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYW protein) GKGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympkk atelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfc qsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQ APGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTA VYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsDIVLTQSPASLAVSLG QRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARFSGS GSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLElKggggsggggsggggs QVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRPGQGLEWIGVIN PGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVYFCARWRGDG YYAYFDVWGAGTTVTVSSHHHHHHEPEA 61 ACP28 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsk (IL2 fusion nfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggg protein) gsggggsggggsggggsggggsQVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWVKQRP GQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAV YFCARWRGDGYYAYFDVWGAGTTVTVSSggggsggggsggggsDIVLTQSPASLAV SLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARF SGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLEIKggggsggggsgg ggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSS ISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSV SSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSID IMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSL KPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHHEPEA 62 ACP29 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinla (IL2 fusion qsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLP protein) GSggggsggggsggggsggggsggggsDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQ QKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQS NEDPYTFGGGTKLEIKggggsggggsggggsQVQLQQSGAELVRPGTSVKVSCKASG YAFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSST AYMQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTVSSggggsggggsg gggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVS SISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS VSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSI DIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMN SLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHHEPEA 63 IL2Ra 10  20   30    40   50 MDSYLLMWGL LTFIMVPGCQ AELCDDDPPE IPHATFKAMA YKEGTMLNCE   60  70    80   90  100 CKRGFRRIKS GSLYMLCTGN SSHSSWDNQC QCTSSATRNT TKQVTPQPEE   110  120   130  140  150 QKERKTTEMQ SPMQPVDQAS LPGHCREPPP WENEATERIY HFVVGQMVYY   160  170   180  190  200 QCVQGYRALH RGPAESVCKM THGKTRWTQP QLICTGEMET SQFPGEEKPQ   210  220  230  240   250 ASPEGRPESE TSCLVTTTDF QIQTEMAATM ETSIFTTEYQ VAVAGCVFLL   260  270 ISVLLLSGLT WQRRQRKSRR TI 64 IL2Rb 10  20   30    40  50 MAAPALSWRL PLLILLLPLA TSWASAAVNG TSQFTCFYNS RANISCVWSQ   60   70   80   90    100 DGALQDTSCQ VHAWPDRRRW NQTCELLPVS QASWACNLIL GAPDSQKLTT   110   120   130  140  150 VDIVTLRVLC REGVRWRVMA IQDFKPFENL RLMAPISLQV VHVETHRCNI   160   170   180  190   200 SWEISQASHY FERHLEFEAR TLSPGHTWEE APLLTLKQKQ EWICLETLTP   210   220  230   240   250 DTQYEFQVRV KPLQGEFTTW SPWSQPLAFR TKPAALGKDT IPWLGHLLVG   260   270  280   290   300 LSGAFGFIIL VYLLINCRNT GPWLKKVLKC NTPDPSKFFS QLSSEHGGDV   310   320  330   340   350 QKWLSSPFPS SSFSPGGLAP EISPLEVLER DKVTQLLLQQ DKVPEPASLS   360   370  380   390   400 SNHSLTSCFT NQGYFFFHLP DALEIEACQV YFTYDPYSEE DPDEGVAGAP   410   420  430   440   450 TGSSPQPLQP LSGEDDAYCT FPSRDDLLLF SPSLLGGPSP PSTAPGGSGA   460   470  480   490   500 GEERMPPSLQ ERVPRDWDPQ PLGPPTPGVP DLVDFQPPPE LVLREAGEEV   510   520  530   540   550 PDAGPREGVS FPWSRPPGQG EFRALNARLP LNTDAYLSLQ ELQGQDPTHL V 65 IL2Rg 10  20   30    40  50 MLKPSLPFTS LLFLQLPLLG VGLNTTILTP NGNEDTTADF FLTTMPTDSL   60   70   80   90    100 SVSTLPLPEV QCFVFNVEYM NCTWNSSSEP QPTNLTLHYW YKNSDNDKVQ   110    120   130  140  150 KCSHYLFSEE ITSGCQLQKK EIHLYQTFVV QLQDPREPRR QATQMLKLQN   160    170   180  190  200 LVIPWAPENL TLHKLSESQL ELNWNNRFLN HCLEHLVQYR TDWDHSWTEQ   210    220   230  240  250 SVDYRHKFSL PSVDGQKRYT FRVRSRFNPL CGSAQHWSEW SHPIHWGSNT   260    270   280  290  300 SKENPFLFAL EAVVISVGSM GLIISLLCVY FWLERTMPRI PTLKNLEDLV   310    320  330  340   350 TEYHGNFSAW SGVSKGLAES LQPDYSERLC LVSEIPPKGG ALGEGPGASP   360 CNQHSPYWAP PCYTLKPET 66 ACP04 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwadqssevlgsgktltiqvkefgdagqytchkggevlshs (human llllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd p40/murine nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt p35 IL12 wstphsyfsltfcvqvqgkskrekkdwftdktsatvicrknasisvraqthyyssswsewasvpcsggggsggggsggggs fusion rvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgs protein) clppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgead pyrvkmklcillhafstrvvtinrvmgylssaHHHHHH 67 ACP05 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwadqssevlgsgktltiqvkefgdagqytchkggevlshs (human llllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd p40/murine nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt p35 IL12 wstphsyfsltfcvqvqgkskrekkdwftdktsatvicrknasisvraqthyyssswsewasvpcsggggsggggsgg fusion ggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypctseeidheditkdktstveaclpleltknesclnsre protein) tsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllmdpkrqifldqnmlavidelmqalnfnsetvpqk ssleepdfyktkiklcillhafriravtidrvmsylnasHHHHHH 68 ACP06 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ (human RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK p40/murine VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV p35 IL12 RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE fusion DTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsggggsggggsggggsSGG protein) PGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqssevlgsgktltiqvkef gdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssd pqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlql kplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqthyyssswsew asvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktcl plelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelm qslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQ LVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGR DTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSSHHHHHHEPEA 69 ACP07 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ (human RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK p40/murine VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV p35 IL12 RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE fusion DTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsggggsggggsggggsSGG protein) PGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqssevlgsgktltiqvkef gdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssd pqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavificlkyenytssffirdiikpdppknlql kplknsrqvevsweypdtwstphsyfshfcvqvqgkskrekkdrvftdktsatvicrknasisvraqchyyssswsew asvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktcl plelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelm qslnhngetlrqkppvgeadpyrvkmlcicillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQ LVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGR DTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMA WYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKP EDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHHEPEA 70 ACP08 QVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIIN (human SVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIY p40/murine WGQGTQVTVSSggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSN p35 IL12 TVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEA fusion DYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPG protein) RSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggg gsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemv vltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktf liceaknysgrftcwwlttistdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpiev mvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfshfcvqvqgkskrekkdr vftdktsatvicrknasisvraqchyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttdd mvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkm yqtefclainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinry mgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFG MSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNS LRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 71 ACP09 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (human GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS p40/murine SQGTLVTVSSggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTV p35 IL12 KWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADY fusion YCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRS protein) LRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRF TISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsg gggsggggsggggsggggsggggsSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvitc dtpeedgitwadqssevlgsgktltiqvkefgdagqytchkggevlshsllllhldcedgiwstdilkdqkepknktflice aknysgrftcwwlttistdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmv davhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfslifcvqvqgkskrekkdrvftd ktsatvicrknasisvraqthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvkt areklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtef qainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgyls saHHHHHHEPEA 72 ACP10 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (human GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS p40/murine SQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtl p35 IL12 dqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcw fusion wittistdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyeny protein) tssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrkna sisvraqthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhyscta edidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnh qqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPA GMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCS GSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAIT GLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVES GGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGT MVTVSSHHHHHHEPEA 73 ACP11 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwadqssevlgsgktltiqvkefgdagqytchkggevlshs (human llllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd p40/murine nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt p35 IL12 wstphsyfsltfcvqvqgkskrekkdivfldktsatvicrknasisvraqthyyssswsewasvpcsggggsggggsggggsr fusion vipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgs protein) clppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgead pyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggg gsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLI YYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLF GTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYG MHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMN SLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsggggsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS HHHHHHEPEA 74 IL12 p40         10         20         30         40         50 human MCHQQLVISW FSLVFLASPL VAIWELKKDV YVVELDWYPD APGEMVVLTC (Uniprot         60         70         80         90        100 (Accession DTPEEDGITH TLDQSSEVLG SGKTLTIQVK EFGDAGQYTC HYGGEYLSHS No.        110        120        130        140        150 P29460 LLLHSKKEDG IWSTDILKDQ KEPKNKTFLR CEAKNYSGRF TCWWLTTIST        160        170        180        190        200 DLTFSVKSSR GSSDPQGVTC GAATLSAERV RGDMKEYEYS VECQEDSACP        210        220        230        240        250 AAEESLPIEV MVDAVHKLKY ENYTSSFFIR DIIKPDPPKN LQLKPLKNSR        260        270        280        290        300 QVEVSWEVPD TWSTPHSYFS LTFCVQVQGK SKRSKKDRVF TDKTSATVIC        310        320 RKNASISVRA QDRYYSSSWS EWASVPCS 75 IL12p35         10         20         30         40         50 mouse MCQSRYLLFL ATLALLNHLS LARVIPVSGP ARCLSQSRNL LKTTDDMVKT (Uniprot         60         70         80         90        100 Accession AREKLKHYSC TAEDIIHEDI TRDQTSTLKT CLPLELHKNE SCLATRETSS No.        110        120        130        140        150 P43430 TIRGSCLPPQ KTSLMNTLCL GSIYEDLKMY QTEFQAINAA LQNHNHQQII        160        170        180        190        200 LDKGMLVAID ELMQSLNHNG ETLRQKPPVG EADPYRVKMK LCILLHAFST        210 RVVTINRVMG YLSSA 76 IL12Rb-2

77 IL-12Rb1         10         20         30         40         50 MEPLVTWVVP LLFLFLLSRQ GAACRTSECC FQDPPYPDAD SGSASGPRDL         60         70         80         90        100 RCYRISSDRY ECSWQYEGPT AGVSHFLRCC LSSGRCCYFA AGSATRLQFS        110        120        130        140        150 DQAGVSVLYT VTLWVESWAR MQTEKSPEVT LQLYNSVKYE PPLGDIKVSK        160        170        180        190        200 LAGQLRMEWE TPDNQVGAEV QFRHRTPSSP WKLGDCGPQD DDIESCLCPL        210        220        230        240        250 EMNVAQKFQL PRRQLGSQGS SWSKWSSPVC VPPENPPQPQ VRESVEQLGQ        260        270        280        290        300 DGRRRLTLKE QPTQLELPEG CQGLAPGIEV TYRLQLHMLS CPCKAKATRT        310        320        330        340        350 LHLGKMPYLS GAAYNVAVIS SNQFGPGLNQ TWHIPADTHT EPVALNISVG        360        370        380        390        400 TNGTTMYWPA RAQSMTYCIE WQPVGQDGGL ATCSLTAPQD PDPAGMATYS        410        420        430        440        450 WSRESGAMGQ EKCYYITIFA SAHPEKLTLW STVLSTYKFG GNASAAGTPH        460        470        480        490        500 HVSVKNHSLD SVSVDWAPSL LSTCPGVLKE YVVRCRDEDS KQVSEHPVQP        510        520        530        540        550 TETQVTLSGL RAGVAYTVQV RADTAWLRGV WSQPQRFSIE VQVSDWLIFF        560        570        580        590        600 ASLGSFLSIL LVGVLGYLGL MRAARHLCPP LPIPCASSAI EEPGGKETWQ        610        620        630        640        650 WINPVDFQEE ASLQEALVVE MSWDKGERTE PLEKTELPEG APELALDTEL        660 SLEDGDRCKA KM 78 IL-12p35         10         20         30         40         50 human MCHQQLVISW FSLVFLASPL VAINELKKDV YVVEVDWTYD APGEMVVLTC (Uniprot         60         70         80         90        100 accession DTPEEDDITW TLDQSSEVLG SGKTLTIQVK EFGDAGQYTC HKGGEVLSHS no.        110        120        130        140        150 P29459) LLLLHKKEDG IWSTDILKDQ KEPKNKTFLR CEAKNYSGRF TCWWLTTIST        160        170        180        190        200 DLTFSVKSSR GSSDPQGVTC GAATLSAERV RDGNKEYEYS VECQEDSACP        210        220        230        240        250 AAEESLPIEV MVDAVHKLYK ENYTSSFFIR DIIKPDPPKN LQLKPLKNSR        260        270        280        290        300 QVEVSWEYPD TWSTPHSYFS LTFCVQVQGK SKREKKDRVF TDKTSATVIC        310        320 RKNASISVRA QDRYYSSSWS EWASVPCS 79 IL-12p40         10         20         30         40         50 mouse MCPQKLTISW FAIVLLVSPL MAMWELEKDV YVVEVDWTPD APGETVNLTC (Uniprot         60         70         80         90        100 accession DTPEEDDITW TSDQRHGVIG SGKTLTITVK ELFDAGQYTC HKGGETLSKS no.        110        120        130        140        150 P43432) HLLLHKKENG IWSTEILKNF KNKTFLKCEA PNYSGRFTCS WLVQRNMDLK        160        170        180        190        200 FNIKSSSSSP DSRAVTCGMA SLSAEKVTLD QRDYEKYSVS CQEDVTCPTA        210        220        230        240        250 EETLPIELAL EARQQNKYEN YSTSFFIRDI IKPDPPKNLQ MKPLKNSQVE        260        270        280        290        300 VSWEYPDSWS TPHSYFSLKF FVRIQRKKEK MKETEEGCNQ KGAFLVEKTS        310        320        330 TEVQCKGGNV CVQAQDRYYN SSCSKWACVP CRVRS 80 ACP01 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (mouse GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS IFNg SQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdm fusion kilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvh protein) celpessIrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFG MSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNS LRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 81 ACP02 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (mouse GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS IFNg SQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiis fusion fylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslr protein) krkrsrcSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisf ylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpess likrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT AVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 82 ACP03 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (mouse GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS IFNg SQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmilqsqiis fusion kfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpqvqrqafnelirvvhqllpesslr protein) krkrsrcggggsggggsggggshgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevl kdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGP AGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGK GLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYC TIGGSLSVSSQGTLVTVSSHHHHHH 83 Human         10         20         30         40         50 IFN-g MKYTSYILAF QLCIVLGSLG CYCQDPYVKE AENLKKYFNA GHSDVADNGT (Uniprot         60         70         80         90        100 60Accession LFLGILKNWK EESDRKIMQS QIVSFYFKLF KNFKDDQSIQ KSVETIKEDM No.        110        120        130        140        150 P01579) NVKFFNSNKK KRDDFEKLTN YSVTDLNVQR KAIHELIQVM AELSPAAKTG               160 KRKRSQMLFR GRRASQ 84 Mouse         10         20         30         40         50 IFNg MNATHCILAL QLFLMAVSGC YCHGTVIESL ESLNNYFNSS GIDVEEKSLF (Uniprot         60         70         80         90        100 Accession LDIWRNQQKD GDMKILQSQI ISFYLRLFEV LKDNQAISNN ISVIESHLIT No.        110        120        130        140        150 P01580) TFFSNSKAKK DAFMSIAKFE VNNPQVQRQA FNELIRVVHQ LLPESSLRKR KRSRC 85 ACP30 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR (mouse QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT IFNg AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidv fusion eekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpq protein) vqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLR LSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISR DNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGM KGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvie shlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhcillpesslikrkrsrcSGGPGPAGMKGLPG SEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSHHHHHH 86 ACP31 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (mouse GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS IFNal SQGTLVTVSSSGGPGPAGMKGLPGScdlpqthnlinkraltlkqmrrlsplsclkdrkdfgfpqekvd fusion aqqikkagaipvlseltqqilniftskdssaawnttlldsfendlhqqlndlqgclmqqvgvqefpltqedallavrkyfhri protein) tvylrekkhspcawevvraevwralsssanvlgrlreekSGGPGPAGMKGLPGSEVQLVESGGGL VQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESV KGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHH HHHHEPEA 87 ACP32 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (mouse GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS IFNal SQGTLVTVSSSGGPGPAGMKGLPGScdlpqthnlinkraltlkqmrrlsplsclkdrkdfgfpqekvd fusion aqqikkagaipvlseltqqilniftskdssaawnttlldsfendlhqqlndlqgclmqqvgvqefpltqedallavrkyfhri protein) tvylrekkhspcawevvraevwralsssanvSGGPGPAGMKGLPGSEVQLVESGGGLVQPGN SLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFT ISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHE PEA 88 IFNgR1         10         20         30         40         50 MALLFLLPLV MQGVSRAEMG TADLGPSSVP IPTNVTIESY NMNPIVYWEY         60         70         80         90        100 QIMPQVPVFT VEVKNYGVKN SEWIDACINI SHYYCNISDH VGDPSNSLWV        110        120        130        140        150 RVKARVGQKE SAYAKSEEFA VCRDGKIGPP KLDIRKEEKQ IMIDIFHPSV        160        170        180        190        200 FVNGDEQEVD YDPETTCYIR VYNVYVRMNG SEIQYKILTQ KEDDCDEIQC        210        220        230        240        250 QLAIPVSSLN SQYCVSAEGV LHVWGVTTEK SKEVCITIFN SSIKGSLWIP        260        270        280        290        300 VVAALLLFLV LSLVFICFYI KKINPLKEKS IILPKSLISV VRSAILETKP        310        320        330        340        350 ESKYVSLITS YQPFSLEKEV VCEEPLSPAT VPGMHTEDNP QKVEHTEELS        360        370        380        390        400 SITEVVTTEE NIPDVVPGSH LTPIERESSS PLSSNQSEPG SIALMSYHSR        410        420        430        440        450 MCSESDHSRN GFDTDSSCLE SHSSLSDSEF PPNNKGEIKT EGQELITVIK        460        470        480        490        500 APTSFGYDKP HVLVDLLVDD SGKESLTGYR PTEDSKEFS 89 IFNgR2         10         20         30         40         50 MRPTLLWSLL LLLGVFAAAA AAPPDPLSQL PAPQHPKIRL YNAEQVLSWE         60         70         80         90        100 PVALSNSTRP VVYQVQFKYI DSKWFTADIM SIGVNCTQIT ATECDFTAAS        110        120        130        140        150 PSAGFPMDFN VTLRLRAELG ALHSAWVTMP WFQHYRNVTV GPPENIEVTP        160        170        180        190        200 GEGSLIIRFS SPFDIADTST AFFCYYVHYW EKGGIQQVKG PFRSNSISLD        210        220        230        240        250 NLKPSRVYCL QVQAQLLWNK SNIFRVGHLS NISCYEIMAD ASTELQQVIL        260        270        280        290        300 ISVGTFSLLS VLAGACFFLV LKYRGLIKYW FHTPPSIPLQ IEEYLKDPTQ        310        320        330        340        350 FILEALDKDS SPKDDVWDGV SIISFPEKEQ EDVLQTL 90 ACP51 QVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITR Mouse IFG GGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYW fusion GKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKF protein GMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMN SLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtvieslesln nyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsi akfevnnpqvqrqafnelirvvhqllpessIrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLV QPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVK GRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHH HHH 91 ACP52 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS Mouse IFG GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS fusion SQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdm protein kilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhq llpessIrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFG MSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNS LRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSEVQLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLY AESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTV SSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQA PGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVY YCNALYGTDYWGKGTQVTVSSHHHHHH 92 ACP53 eahkseiahryndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlr Mouse IFG enygeladcctkqepemecflqlikddnpslppferpeaeamctsfkenpttfmghylhevarrlipyfyapellyyaeq fusion yneiltqccaeadkescltpkldgvkekalvssvrqrmkcssmqkfgerafkawavarlsqtfpnadfaeitklatdltkv protein nkecchgdllecaddraelakymcenqatissklqtccdkpllkkahclsevehdtmpadlpaiaadfVedqevckny aeakdvflgtflyeysrrhpdysvslllrlakkyeatlekccaeanppacygtvlaefqplveepknlvktncdlyeklgey gfqnailvrytqkapqvstpUveaamlgrvgtkcctlpedqrlpcvedylsailnrvcllhektpvsehvtkccsgslver rpcfsaltvdetyvpkefkaetftflisdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdt cfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleshmyfiissgidveekslfldiwrnwqkdgdmkilqsq iisfylrlfevlkdiiqaismiisvieshlittffsiiskakkdafmsiakfevmipqvqrqafnelirvvliqllpes slrkrkrsrcSGGPGPAGMKGLPGSeahkseiahiyndlgeqhfkglvliafsqylqkcsydehaklvqevtd faktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepemecflqhkddnpslppferpeaeamctslk enpttfmghylhevarrhpyiyapellyyaeqyneiltqccaeadkescltpkldgvkekalvssvrqrmkcssmqkf gcrafkawavarlsqtfpnadfaeitklatdltkvnkecchgdllecaddrackikymccnqatissklqtccdkpllkka hclsevehdtmpadlpaiaadfVedqevcknyaeakdvflgtflyeysrrhpdysvslllrlakkyeatlekccaeanpp acygtvlaefqplveepknlvktncdlyeklgeygfqnailvrytqkapqvstpUveaamlgrvgtkcctlpedqrlpcv edylsailnrvcllhcktpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftnisdictlpekekqikkqtalaelv klikpkalaeqlktvmddfaqfldtcckaadkdtcfstegpulvtrckdalaHHHHHH 93 ACP54 eahkseiahiyndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlr Mouse IFG enygeladcctkqepemecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeq fusion yneiltqccaeadkescltpkldgvkekalvssviqrmkcssmqkfgerafkawavarlsqtfpnadfaeitklatdltkv protein nkecchgdllecaddraelakymcenqatissklqtccdkpllkkahclsevehdtmpadlpaiaadfVedqevckny aeakdvflgtflyeysrrhpdysvslllrlakkyeatlekccaeanppacygtvlaefqplveepkiilvktncdlyeklgey gfqnailviytqkapqvstptiveaarnlgrvgtkcctlpedqrlpcvedylsailmvcllhektpvsehvtkccsgslver rpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdt cfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtvieslesliinyfussgidveekslfldiwrnwqkdgd mkilqsqiisfylrlfevlkdnqaismiisvieshlittffsnskakkdafnisiakfevmipqvqrqafnelirvvhqllpes slrkrkrsrcggggsggggsggggshgtviesleslnnyfnssgidveekslfldiwmwqkdgdmkilqsqiisfylrlf evlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGP GPAGMKGLPGSeahkseiahiyndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaanc dkslhtlfgdklcaipiilrenygeladcclkqepeniecflqhkddnpslppferpeaeamctsfkenpttfmghylhev arrhpyfyapellyyaeqyneiltqccaeadkescltpkldgvkekalvssvrqnnkcssmqkfgerafkawavarlsq tfpnadfaeitklatdltkvnkecchgdllecaddraelakymcenqatissklqtccdkpllkkahclsevehdtmpadl paiaadfvedqevckiiyaeakdvflgtflyeysrrhpdysvslllrlakkyeatlekccaeanppacygtvlaefqplvee pknlvktncdlyeklgeygfqnailviytqkapqvstptlveaamlgrvgtkcctlpedqrlpcvedylsailnrvcllhe ktpvsehvtkccsgslverrpcfsaltvdetyvpkefkaetftfhsdictlpekekqikkqtalaelvkhkpkataeqlktv mddfaqfldtcckaadkdtcfstegpnlvtrckdalaHHHHHH 94 ACP50 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR Mouse QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG IFG VYYCNALYGTDYWGKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNS fusion LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI protein SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGShgtviesleslnnyfrissgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvies hlittffsnskaldcdafmsiakfevnnpqvqrqafnelirvvhqllpesslitcrlcrsreggggsggggsggggshgtv iesleslnnyfussgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskak lulafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVES GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSHHHHHH 95 ACP55 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT IFG AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidv fusion eekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpq protein vqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLR LSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISR DNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGM KGLPGShgtviesleslnnyfrissgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvie shlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPG SEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSHHHHHH 96 ACP56 mclmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY Mouse IFG RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT fusion AVYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNS protein LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGShgtviesleslnnyfrissgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisv ieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLP GSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSS ISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSV SSQGTLVTVSSHHHHHHEPEA 97 ACP57 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT IFG AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidv fusion eekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpq protein vqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLR LSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISR DNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsgggg sQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIIN SVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIY WGQGTQVTVSSHHHHHHEPEA 98 ACP58 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse IFGQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT fusion AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidv protein eekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpq vqrqafnelirvvhqllpesshicrkrsrcSGGPGPAGMKGLPGShgtviesleslnnyfrissgidveekslfldi wrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpqvqrqafnel irvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAAS GFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTT LYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQ ESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISY DDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQV TVSSHHHHHHEPEA 99 ACP59 mclmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY Mouse IFG RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT fusion AVYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNS protein LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGShgtviesleslnnyfrissgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisv ieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLP GShgtviesleslnnyfrissgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisviesh littffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslikrkrsrcSGGPGPAGMKGLPGSEVQ LVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGR DTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSSHHHHHHEPEA 100 ACP60 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT IFG AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidv fusion eekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpq protein vqrqafnelirvvhqllpesshicrkrsrcSGGPGPAGMKGLPGShgtviesleslnnyfrissgidveekslfldi wrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpqvqrqafnel irvvhqllpesslikrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAAS GFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTT LYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQ ESGGGLAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTN YADSVKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQ VTVSSHHHHHHEPEA 101 ACP61 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse IFG QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT fusion AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidv protein eekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpq vqrqafnelirvvhqllpesslikrkrsrcSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldi wrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpqvqrqafnel irvvhqllpesslikrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAAS VGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTT LYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGS TYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGVGAFRPYRKH EWGQGTLVTVSRggggsggggsggggsSSELTQDPAVSVALGQTVRITCQGDSLRSY YASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTTTGAQAEDEA DYYCNSSPFEENLVVFGGGTKLTVLHHHHHHEPEA 102 ACP63 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVR Anti-FN QAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED CGS-2 TAVYYCARGVGAFRPYRKHEWGQGTLVTVSRggggsggggsggggsSSELTQDPAV scFv SVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSG SSSGNTASLTTTGAQAEDEADYYCNSSPFEHNLVVFGGGTKLTVLHHHHHHE PEA 103 ACP69 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse IFG QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT fusion AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidv protein eekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpq vqrqafnelirvvhqllpesslikrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLR LSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISR DNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGM KGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvie shlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesshkrkrsrcHHHHHHEPEA 104 ACP70 mdmrvpaqllglllwlrgarchgtviesleslnnyfnssgidveekslfkliwrnwqkdgdmkilqsqiisfylrlfevlk Mouse IFG dnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesshkrkrsrcSGGPGP fusion AGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGK protein GLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYC TIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldi wrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpqvqrqafnel irvvhqllpesslikrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAAS GFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTT LYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 105 ACP71 mdmrvpaqllglllwlrgarchgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlk Mouse IFG dnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesshkrkrsrcSGGPGP fusion AGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLV QEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQE PERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPY proteinFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKC SSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLE CADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPA IAADFVEDQEVCKNYAEAKDVFLGlFLYEYSRRHPDYSVSLLLRLAKKYEAT LEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILV RYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCL LHEKTPVSEHVIKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTL PEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCF STEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnyfassgidveekslfldiwrn wqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpqvqr qafneliryvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAF SQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPN LRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPT TFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDG VKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLAT DLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAH CLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPD YSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNC DLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQ RLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYV PKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDF AQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAHHHHHHEPEA 106 ACP72 mdmrvpaqllglllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDE Mouse IFG HAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADC fusion CTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVA protein RRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQ RMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCH GDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMP ADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAK KYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGF QNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAI LNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFH SDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAA DKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnythssgidveekslfld iwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvq rqafnelirvvhqllpesslitcrkrsrcSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFK GLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGD KLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCT SFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCL TPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFA EITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDK PLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYE YSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKN LVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCC TLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALT VDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLK TVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtvie sleslnnyfassgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlitt ffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcHHHHHHEPEA 107 ACP73 mdmrvpaqllglllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDE Mouse IFG HAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADC fusion CTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVA RRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQ RMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCH proteinGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMP ADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAK KYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGF QNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAI LNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFH SDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAA DKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnythssgidvee kslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafms iakfevnnpqvqrqafnelirvvhqllpesslitcrkrsrcSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFK GLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGD KLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCT SFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCL TPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFA EITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDK PLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYE YSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKN LVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCC TLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALT VDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLK TVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGL PGShgtviesleslnnyfrissgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlitt ffsnskaldcdafmsiakfevnnpqvqrqafnelirvvhqllpesslrkrkrsrcSGGPGPAGMKGLPGSEA HKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCV ADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHK DDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAE QYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAF KAWAVARLSQIFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKY MCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEV CKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPP ACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVS TPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEH VTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQ TALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTR CKDALAHHHHHHEPEA 108 ACP74 mdmrvpaqllglllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDE Mouse IFG HAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADC fusion CTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVA protein RRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQ RMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCH GDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMP ADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAK KYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGF QNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAI LNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFH SDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAA DKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnythssgidvee kslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvq rqafnelirvvhqllpesslitcrkrsrcSGGPGPAGMKGLPGSggggsEAHKSEIAHRYNDLGEQ HFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTL FGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEA MCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADK ESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPN ADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQT CCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGT FLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVE EPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVG TKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCF SALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAE QLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAggggsSGGPGP AGMKGLPGShgtviesleslnnythssgidveekslfldiwrnwqk dgdmkilqsqiisfylrlfevlkdnqaisn nisvieshlittffsnslcaldcdafmsiakfevnnpqvqrqafne lirvvhqllpesslrkrkrsrcSGGPGPAGMK GLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTD FAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNEC FLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPEL LYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKF GERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRA ELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVE DQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAE ANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKA PQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTP VSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQI KKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPN LVTRCKDALAHHHHHHEPEA 109 ACP75 mdmrvpaqllglllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDE Mouse IFG HAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADC fusion CTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVA RRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQ RMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCH proteinGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMP ADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAK KYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGF QNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAI LNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFH SDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAA DKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGShgtviesleslnnyth ssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnni svieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhq llpesshicrkrsrcSGGPGPAGMKGLPGSggggsggggsEAHKSEIAHRYND LGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKS LHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPE AEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAE ADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQT FPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKL QTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFL GTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPL VEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGR VGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERR PCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKA TAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAggggsgggg sSGGPGPAGMKGLPGShgtviesleslnnythssgidveekslfldiwrnwq kdgdmkilqsqiisfylrlfe vlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqaf nelirvvhqllpesslikrkrsrcSGGP GPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAK LVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTK QEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRH PYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRM KCSSMQKFGERAFKAWAVARLSQIFPNADFAEITKLATDLTKVNKECCHGDL LECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADL PAIAADFVEDQEVCKNYAEAKDVFLGIFLYEYSRRHPDYSVSLLLRLAKKYE ATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAI LVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRV CLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDIC TLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDT CFSTEGPNLVTRCKDALAHHHHHHEPEA 110 ACP78 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse IFG QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT fusion AVYYCTIGGSLSVSSQGTLVTVSSggggsggggsgggg protein shgtviesleslnnythssgidveekslfld iwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisv ieshlittffsnskaldcdafmsiakfevnnpqvqrqafne lirvvhqllpesslrkrkrsreggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTF SKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYL QMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggshgtviesleslnn ythssgidveekslildiwrnwqkdgdmkilqsqiisfylrlfevlkd nqaisnnisvieshlittffsnskakkdafmsia kfevnnpqvqrqafnelirvvhqllpesslrkrkrsreggggsggggsggggsEVQLVESGGGLVQPGNS LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEP EA 111 ACP 134 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse IFG QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT fusion AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidv protein eekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisn nisvieshlittffsnskaldcdafmsiakfevnnpq vqrqafnelirvvhqllpesshkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLR LSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISR DNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGM KGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvie shlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesshkrkrsrcSGGPGPAGMKGLPG SEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSNS VMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNN LKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHHEPEA 112 ACP135 mdmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY Mouse IFG RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT fusion AVYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNS protein LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisv ieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesshkrkrsrcSGGPGPAGMKGLP GSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSS ISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSV SSQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgd mkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkda fmsiakfevnnpqvqrqafnelirvvhqllpes shkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKF GMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMN SLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 113 ACP34 mdmrvpaqllglllwlrgarcrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclp Mouse IL- lelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmq 12 fusion slnhngetlrqkppvgeadpyrvkmklcillhafstryvtinrvmgylssaSGGPGPAGMKGLPGSmwele protein kdvyvvevdwtpdapgetvnitcdtpeedditwtsdqrhgvigsgktltitykefldagqytchkggetlshshlllhkke ngiwsteilknfknktflkceapnysgrftcswlvqrnmdlkfnikssssspdsravtcgmaslsaekvtldqrdyekys vscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevsweypdswstphsyfsl kffvriqrkkekmketeegcnqkgaflvektstevqckggnvcvqaqchyynsscskwacvpervrsHHHHHH 114 ACP35 mdmrvpaqllglllwlrgarcrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclp Mouse IL- lelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmq 12 fusion slnhngetlrqkppvgeadpyrvkmklcillhafstryvtinrvmgylssaggggsggggsggggsSGGPGPAG protein MKGLPGSggggsggggsggggsmwelekdvyvvevdwtpdapgetvnitcdtpeedditwtsdqrhgvigsg ktltitykefldagqytchkggetlshshlllhkkengiwsteilknfkatflkceapnysgrftcswlvqrnmdlkfnik ssssspdsravtcgmaslsaekvtldqrdyekysyscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdpp knlqmkplknsqvevsweypdswstphsyfslkffvriqrkkekmketeegcnqkgaflvektstevqckggnvcv qaqdryynsscskwacvpervrsHHHHHH 115 ACP36 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse IL- QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT 12 fusion AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSmwelekdvyvvevdwtpd protein apgetvnhcdtpeedditwtsdqrhgvigsgktltitykefldagqytchkggetlshshlllhkkengiwsteilknfkn kffikceapnysgrftcswlvqrnmdlkfnikssssspdsravtcgmaslsaekvtldqrdyekysyscqedvtcptaee tlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevsweypdswstphsyfslkffvriqrkkekm keteegcnqkgaflvektstevqckggnvcvqaqchyynsscskwacvpervrsggggsggggsggggsrvipvsgparcl sqsrifilkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktsl mmticlgsiyedlkmyqtefciainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmkl cillhafstryvtinrvmgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSC AASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNA KTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 116 ACP37 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR Mouse IL- QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG 12 fusion VYYCNALYGTDYWGKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNS protein LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGSmwelekdvyvvevdwtpdapgetvnitcdtpeedditwtsdqrhgvigsgktltitykefldagqytc hkggetlshshlllhkkengiwsteilknfknktflkceapnysgrftcswlvqrnmdlkfnikssssspdsravtcgmas Vlsaekvtldqrdyekysyscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevs weypdswstphsyfslkffvriqrkkekmketeegcnqkgaflvektstevqckggnvcvqaqchyynsscskwac vpervrsggggsggggsggggsrvipvsgparclsqsnillkttddmvktareklkhysctaedidheditrdqtstlktcl plelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiildkgmlvaidelm qslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQ LVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGR DTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSSHHHHHH 117 ACP79 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR Mouse IL- QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG 12 fusion VYYCNALYGTDYWGKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNS protein LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGSmwelekdvyvvevdwtpdapgetvnitcdtpeedditwtsdqrhgvigsgktltitykefldagqytc hkggetlshshlllhkkengiwsteilknfknktflkceapnysgrftcswlvqrnmdlkfnikssssspdsravtcgmas lsaekvtldqrdyekysyscqedvtcptaeetlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevs weypdswstphsyfslkffvriqrkkekmketeegcnqkgaflvektstevqckggnvcvqaqchyynsscskwac vpervrsggggsggggsggggsrvipvsgparclsqsnillkttddmvktareklkhysctaedidheditrdqtstlktcl plelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiildkgmlvaidelm qslnhngetlrqkppvgeadpyrvkmlcicillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQ LVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGR DTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSSHHHHHH 118 ACP80 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse IL- QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT 12 fusion AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSmwelekdvyvvevdwtpd protein apgetvnhcdtpeedditwtsdqrhgvigsgktltitykefldagqytchkggetlshshlllhkkengiwsteilknfkn kffikceapnysgrftcswlvqrnmdlkfnikssssspdsravtcgmaslsaekvtldqrdyekysyscqedvtcptaee tlpielalearqqnkyenystsffirdiikpdppknlqmkplknsqvevsweypdswstphsyfslkffvriqrkkekm keteegcnqkgaflvektstevqckggnvcvqaqdwynsscskwacvpervrsggggsggggsggggsrvipvsgparc lsqsnillkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktsl mmticlgsiyedlkmyqtefciainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmkl cillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSC AASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNA KTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQV QLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGG TISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGK GTQVTVSSHHHHHH 119 ACP91 mdmrvpaqllglllwlrgarciwelkkdvyvveldwypdapgemvvitcdtpeedgitwildqssevlgsgkfltiqv Chimeric kefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistditfsvkssrg IL-12 ssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppkn fusion lqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqchyysssws protein ewasvpcsggggsggggsggggsrvipvsgparclsqsnillkttddmvktareklkhysctaedidheditrdqtstlkt clplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidel mqslnhngetlrqkppvgeadpyrvkmklcillhafstivvtinrvmgylssaggggsggggsggggsggggsgggg sggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQ QLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQS YDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLS CAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggggsgg ggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSS ISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSV SSQGTLVTVSSHHHHHHEPEA 120 ACP136 mdmrvpaqllglllwlrgarciwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqssevlgsgkfltiqv Chimeric kefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistditfsvkssrg IL-12 ssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklIcyenytssffirdiikpdppkn fusion lqlkplknsrqvevsweypdtwstphsyfshfcvqvqgkskrekkdrvftdktsatvicrknasisvraqchyysssws protein ewasvpcsggggsggggsggggsrvipvsgparclsqsnillkttddmvktareklkhysctaedidheditrdqtstlkt clplelhIcnesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidel mqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggg gsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVK WYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYY CQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSL RLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHH HEPEA 121 ACP138 mdmrvpaqllglllwlrgarciwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqssevlgsgktltiqv Chimeric kefgdagqytchkggevlshsllllhIckedgiwstdilkdqkepknktflrceaknysgrftcwwlttistditfsvkssrg IL-12 ssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklIcyenytssffirdiikpdppkn fusion lqlkplknsrqvevsweypdtwstphsyfshfcvqvqgkskrekkdrvftdktsatvicrknasisvraqchyysssws protein ewasvpcsggggsggggsggggsrvipvsgparclsqsnillkttddmvktareklkhysctaedidheditrdqtstlkt clplelhIcnesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidel mqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggg gsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVK WYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYY CQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSL RLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSggggsggg gsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEW VSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGS LSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFT VSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYL QMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHHEPEA 122 ACP139 mdmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY Chimeric RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT IL-12 AVYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsiwelIckdvyvveldwypdapgem fusion vvitcdtpeedgitwadqssevlgsgktltiqvkefgdagqytchkggevlshsllllhldcedgiwstdilkdqkepknk protein tflrceaknysgrftcwwlttistclitfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpie vmvdavhklIcyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkd rvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttdd mvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkm yqtefgainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinry mgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVS GAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFS GSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggg gsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLE WVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKT HGSHDNWGQGTMVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCA ASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 123 ACP140 mdmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY Chimeric RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT IL- AVYVCNRNFDRIYWGQGTQVTVSSSGGPGPAGMKGLPGSiwelkkcIvyvveldwyp 12 dapgemvvitcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshsllllhIckedgiwstdilkdq fusion kepknkttflrceaknysgrftcwwlttistdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpa protein aeeslpievmvdavhklIcyenytssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgk skrekkdrvftdktsatvicrknasisvraqchyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsr nllkttddmvktareklkhysctaedidheditrdqtstlktclplelhIcnesclatretssttrgsclppqktslmmticlgsi yedlkmyqtefgainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstry vtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQP PSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPD RFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLgggg sggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKG LEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC KTHGSHDNWGQGTMVTVSSggggsggggsggggsEVQLVESGGGLVQPGNSLRLSC AASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNA KTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 124 ACP38 mclmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGL EWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR DSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVG DRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsEVQLV ESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDT LYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLV TVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRLSCAASGRlFSIDIMSWYR QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG VYYCNALYGTDYWGKGTQVTVSSHHHHHH 125 ACP39 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG fusion VYYCNALYGTDYWGKGTQVTVSSSGGPGPAGMKGLPGSEVQLVESGGGLVQ protein PGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPG PAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPG KGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYY CARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSA SVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSG SGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGL PGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympkkatelkhlqcleeelkpleevinlaqsknf hlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltHHHHHH** 126 ACP40 mdmrvpaqllglllwlrgarcelcdddppeiphatfkamaykegtmlnceckrgfrriksgslymktgnsshsswd IL-2 fusion nqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcv qgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtddfqiqtemaatmets proteiniftteyqggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSaptssstkktqlqlehllld lqmilnginnyknpkltrmlffidympldcatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettf mceyadetativeflnrwitfcqsiistltHHHHHH 127 ACP41 mclmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSggggsggggsggggsggggsggggsggggselcdddppeiphallkamaykegtmlnceckrgfr (WW0076) riksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppwen eateriyhfvvgqmvyyqcvqgyralhrgpaesvclunthgktrwtqpqlictgemetsqfpgeekpqaspegrpese tsclvtdclfqiqtemaatmetsiftteyqHHHHHH 128 ACP42 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR IL-2 QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT fusion AVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggselcdddppeiphatfkamaykegtmln protein ceckrgfrriksgslymktgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcre (WW0078) pppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqasp egrpesetsclvtdclfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggsSGGPGPAG MKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinl aqsknfblrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltHHHHHH 129 ACP43 mclmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSggggsggggsggggsggggsggggsggggselcdddppeiphallkamaykegtmlnceckrgfr (WW0079) riksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppwen eateriyhfvvgqmvyyqcvqgyralhrgpaesvclunthgktrwtqpqlictgemetsqfpgeekpqaspegrpese tsclvtddfqiqtemaatmetsiftteyqggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCA ASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 130 ACP44 mclmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSggggsggggsggggsggggsggggsggggselcdddppeiphatikamaykegtmlnceckrgfr (WW0080) riksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppwen eateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpese tsclvtddfqiqtemaatmetsiftteyqSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLR LSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISR DNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 131 ACP45 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR IL-2 QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT fusion AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSEVQLVESGGGLVQP (WW0046) proteinGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRF TISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSG GGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQ KPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYY TYPYTFGGGTKVEIKggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSa ptssstkktqlqlehllldlqmilnginnyknpkihmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrprd lisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 132 ACP46 mclmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCA ASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKN SLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpgpagmkglp gsDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSA SFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEI KggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQA PGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV YYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLVQAGGSLRL SCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVKGRFTISRDNA KNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSHHHHHH 133 ACP47 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG fusion VYYCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptssstkktqlqlehllldlqmilngin proteinnyknpkltrmltfklympldcatelkhlqcleeelkpleevinlaqsknfhlrprd lisninvivlelkgsettfmceyadet ativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAAS GFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTT LYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsgg ggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGD RVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 134ACP48 mclmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGL (WW0054) EWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR DSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVG DRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsEVQLV ESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDT LYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLV TVSSHHHHHH 135 ACP49 mclmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSggggsggggsggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCA (WW0055) ASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKN SLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGG SGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKA LIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGG TKVEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSW VRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPE DTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 136 ACP92 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR IL-2 fusion QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT proteinAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlqm ilnginnyknpklirmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmce yadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSC AASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNA KTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 137 ACP93 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG protein VYYCNALYGTDYWGKGTQVTVSSgsgsgsgsgsgsgsgsEVQLVESGGGLVQPGNS LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgsgsgsgsgsgs gsgsQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVAR ITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTD YWGKGTQVTVSSgsgsgsgsgsgsgsgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASF RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK SGGPGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcl eeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltHHHHHH 138 ACP94 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG protein VYYCNALYGTDYWGKGTQVTVSSgsgsgsgsgsgsgsgsEVQLVESGGGLVQPGNS LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgsgsgsgsgsgs gsgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVA AIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNW DALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTI TCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSaptssstk ktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfblrprdlisninv ivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 139 ACP95 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG protein VYYCNALYGTDYWGKGTQVTVSSgsgsgsgsgsgsgsgsEVQLVESGGGLVQPGNS LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinl aqsknfblrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltHHHHHH 140 ACP96 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG protein VYYCNALYGTDYWGKGTQVTVSSSGGPGPAGMKGLPGSaptssstkktqlqlehllldlq milnginnyknpklirmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfm ceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRL SCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRD NAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 141 ACP97 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG protein VYYCNALYGTDYWGKGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNS LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGSaptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelklilqcleeelkpleevinl aqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGS EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSHHHHHH 142 ACP99 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG protein VYYCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptsssticktqlqlehllldlqmilngin nyknpkltrmltficfympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadet ativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAAS GFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTT LYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 143 ACP100 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG protein VYYCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptsssticktqlqlehllldlqmilngin nyknpkltrinifficfympldcatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgset tfmceyadetativeflnrwitfcqsiistltHHHHHH 144 ACP101 mdmrvpaqllglllwlrgarcaptsssticktqlqlehllldlqmilnginnyknpkltrmlafympkkatelkhlqcle (WW0061) eelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAG IL-2 fusion MKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGL protein EWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTI GGSLSVSSQGTLVTVSSHHHHHH 145 ACP102 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG protein VYYCNALYGTDYWGKGTQVTVSSSGGPGPAGMKGLPGSaptsssticktqlqlehllldlq milnginnyknpkltrmlafympkkatelkhlqcleeelkpleevinlaqsknfhliprdlisninvivlelkgsettfm ceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRL SCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRD NAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggs ggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPG KGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYY CARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSA SVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSG SGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 146 ACP103 mdmrvpaqllglllwlrgarcaptsssticktqlqlehllldlqmilnginnyknpkltrmla IL-2 fusion fympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmcey protein adetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsg gggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVR GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGG SGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKA LIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGG TKVEIKggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSW VRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPE DTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGG SLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTIS RDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHH 147 ACP104 mdmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY IL-2 fusion RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT protein AVYVCNRNFDRIYWGQGTQVTVSSaptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfy mpkkatelklilqcleeelkpleevlnlaqsknflilrprdlisninvivlelkgsettfmceyadetati veflnrvvitfcqsiieflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSC AASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLR PEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsEVQL VESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYT YSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWG QGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNV GTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 148 ACP105 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVR IL-2 fusion QAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTA protein VYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggg gsggggsggggsggggsSGGPGPAGMKGLPGSaptsssticktqlqlehllldlqmilnginnyknpkltrml tflcfympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadeta tiveflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFG MSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNS LRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsQVQLQESGGGLA QAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVK GRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSH HHHHH 149 ACP106 mdmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY IL-2 fusion RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT protein AVYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNS LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGL EWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR DSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVG DRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggggsgg ggsggggsSGGPGPAGMKGLPGSaptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkk atelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwil fcqsiistltHHHHHH 150 ACP107 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVR IL-2 fusion QAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTA protein VYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggg gsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQA PGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAV YYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGSaptsssticktqlqlehllldlqmilng innyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhliprdlisninvivlelkgse ettfmceyadtativeflnrwitfcqsiistltggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFT VSNSVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYL QMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHH 151 ACP108 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG protein VYYCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptsssticktqlqlehllldlqmilngin nyknpkltrmltfklympldcatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsett fmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSrgetgpaaPGSEVQLVESGGGLVQPGNS LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsg gggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQ APGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAV YYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSL SASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 152 ACP117 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVR Anti-FN QAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED CGS-2 PEATAVYYCARGVGAFRPYRKHEWGQGTLVTVSRggggsggggsggggsSSELTQDPAV scFv SVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSG SSSGNTASLTTTGAQAEDEADYYCNSSPFEHNLVVFGGGTKLTVLHHHHHHE 153 ACP118 mdmrvpaqllglllwlrgarcQVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWV NARA1 KQRPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSD Vh/Vl non- DSAVYFCARWRGDGYYAYFDVWGAGTTVTVSSggggsggggsggggsDIVLTQSP cleavable ASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLES GIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLEIKHHH HHHEPEA 154 ACP119 mdmrvpaqllglllwlrgarcQVQLQQSGAELVRPGTSVKVSCKASGYAFTNYLIEWV NARA1 KQRPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKSSSTAYMQLSSLTSD Vh/Vl DSAVYFCARWRGDGYYAYFDVWGAGTTVTVSSSGGPGPAGMKGLPGSDIVL cleavable TQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAAS NLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPYTFGGGTKLEI KHHHHHHEPEA 155 ACP120 mdmrvpaqllglllwlrgarcDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMN NARA1 WYQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYC Vl/Vh non- QQSNEDPYTFGGGTKLEIKggggsggggsggggsQVQLQQSGAELVRPGTSVKVSCK cleavable ASGYAFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKFKGKATLTADKS SSTAYMQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTVSSHHHHH HEPEA 156 ACP121 mdmrvpaqllglllwlrgarcDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMN NARA1 WYQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYC Vl/Vh QQSNEDPYTFGGGTKLEIKSGGPGPAGMKGLPGSQVQLQQSGAELVRPGTSV cleavable KVSCKASGYAFTNYLIEWVKQRPGQGLEWIGVINPGSGGTNYNEKFKGKATL TADKSSSTAYMQLSSLTSDDSAVYFCARWRGDGYYAYFDVWGAGTTVTVSS HHHHHHEPEA 157 ACP124 mdmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmilfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistliggggsggggsg protein gggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVS (WW0159) SISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS VSSQGTLVTVSSHHHHHHEPEA 158 ACP132 mdmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmilfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistliggggsggggsg protein gggsdahksevahrfkdlgeenfkalvliafaqylqqcpfedhvklvnevtefaktcvadesaencdkslhtlfgdklctv (WW0177) atlretygemadccakqepernecflqhkddnpnlprlvrpevdvmctafhdneeffildcylyeiarrhpyfyapellff akrykaafteccqaadkaacllpkldelrdegkassakqrlkcaslqkfgerafkawavarlsqrfpkaefaevsklvtdlt kyhtecchgdllecaddradlakyicenqdsissklkeccekpllekshciaevendempadlpslaadfveskdvckn yaeakdvflgmflyeyarrhpdysvvillrlaktyettlekccaaadphecyakvfdefkplveepqnlikqncelfeqlg eykfqnallviytldwpqvstptivevsrnlgkvgskcckhpeakrmpcaedylsvvinqlcvlhektpvsdrvtkcct esknrrpcfsalevdetyvpkefnaetflfhadictlsekerqildcqtalvelvldikpkatkeqlkavmddfaafvekcc kaddketcfaeegkklvaasqaalglHHHHHHEPEA 159 ACP141 mdmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmilfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistliggggsggggsg protein gggsdahksevahrfkdlgeenfkalvliafaqylqqcpfedhvklvnevtefaktcvadesaencdkslhtlfgdklctv (WW0178) atlretygemadccakqepernecflqhkddnpnlprlvrpevdvmctafhdneeffildcylyeiarrhpyfyapellff akrykaafteccqaadkaacllpkldelrdegkassakqrlkcaslqkfgerafkawavarlsqrfpkaefaevsklvtdlt kyhtecchgdllecaddradlakyicenqdsissklkeccekpllekshciaevendempadlpslaadfveskdvckn yaeakdvflgmflyeyarrhpdysvvillrlaktyettlekccaaadphecyakvfdefkplveepqnlikqncelfeqlg eykfqnallviytldwpqvstptivevsrnlgkvgskcckhpeakrmpcaedylsvvinqlcvlhektpvsdrvtkcct esknrrpcfsalevdetyvpkefnaetflfhadictlsekerqildcqtalvelvldikpkatkeqlkavmddfaafvekcc kaddketcfaeegkklvaasqaalglHHHHHHEPEA 160 ACP142 mdmrvpaqllglllwlrgarcaptssstIcktqlqlehllldlqmilnginnyknpkltrmilflcfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSdaliksevahrfkdlgeenfkalvliafaqylqqcpfedhvklvnevtefaktcvadesaencdkslhtlf (WW0179) gdkletvatlretygemadccakqepernecflqhkddnpnlprlvrpevdvmctafhdneeffildcylyeiarrhpyf yapellffakrykaafteccqaadkaacllpkldelrdegkassakqrlkcaslqkfgerafkawavarlsqrfpkaefaev sklvtdltkvhtecchgdllecaddradlakyicenqdsissklkeccekpllekshciaevendempadlpslaadfves kdvcknyaeakdvflgmflyeyarrhpdysvvillrlaktyettlekccaaadphecyakvfdefkplveepqnlikqn celfeqlgeykfqnallviytkkvpqvstptivevsrnlgIcvgskcckhpeakrmpcaedylsvvinqlcvlhektpvs drytkcctesknripcfsalevdetyvpkefnaelftfhadictlsekerqildcqtalvelvkhkpkatkeqlkavmdclfa afvekcckaddketcfaeegIcklvaasqaalglHHHHHHEPEA 161 ACP144 mdmrvpaqllglllwlrgarcaptssstIcktqlqlehllldlqmilnginnyknpkltrmilflcfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGL EWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTI GGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPG SEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAI DSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDA LDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITC KASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsQVQLQESGGG LAQAGGSLSLSCAASGFTVSNSVMAWYRQTPGKQREFVAIINSVGSTNYADS VKGRFTISRDNAKNTVYLQMNNLKPEDTAVYVCNRNFDRIYWGQGTQVTVS SHHHHHHEPEA 162 ACP145 mdmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY IL-2 fusion RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT protein AVYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsaptssstldctqlqlehllldlqmilngi nnyknpkltrmltfkfympldcatelkhlqcleeelkpleevinlaqsknflilrprdlisninvivlelkgsetlfmceyade tativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAAS GFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTT LYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsgg ggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFR YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKH HHHHHEPEA 163 ACP146 mdmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY IL-2 fusion RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT protein AVYVCNRNFDRIYWGQGTQVTVSSSGGPGPAGMKGLPGSaptssstIcktqlqlehllldlqmilngimi ykiipkltrmltfkfSmpkkatelklilqcleeelkpleevlnlaqsknflilrprdlisninvivlelkgsettfm ceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRL SCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRD NAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggs ggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASG FTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYS ASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHHEPEA 164 ACP133 mdmrvpaqllglllwlrgarcaptssstIcktqlqlehllldlqmilnginnyknpkltrmilfkfympkkatelkhlqcle (WW0196) eelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltHHHHHH IL-2-6xHis (“6xHis” disclosed as SEQ ID NO.: 354) 165 ACP147 mdmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle IL-2 fusion eelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAG protein MKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGL EWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTI GGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPG SEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAI DSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDA LDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITC KASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsQVQLQESGGG LVQAGGSLRLSCAASGRIFSIDIMSWYRQAPGKQRELVARITRGGTISYDDSVK GRFTISRDNAKNTVYLQMNSLKPEDTGVYYCNALYGTDYWGKGTQVTVSSH HHHHHEPEA 166 ACP148 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG fusion VYYCNALYGTDYWGKGTQVTVSSggggsggggsggggsaptsssticktqlqlehllldlqmilngin protein nyknpkltrmlificlympldcatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadet ativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAAS GFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTT LYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsgg ggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFR YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKH HHHHHEPEA 167 ACP149 mdmrvpaqllglllwlrgarcQVQLQESGGGLVQAGGSLRLSCAASGRIFSIDIMSWYR IL-2 fusion QAPGKQRELVARITRGGTISYDDSVKGRFTISRDNAKNTVYLQMNSLKPEDTG proteinVYYCNALYGTDYWGKGTQVTVSSSGGPGPAGMKGLPGSaptsssticktqlqlehllldlq milnginnyknpkltrmlafympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfm ceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRL SCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRD NAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggs ggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASG FTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYS ASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHHEPEA 168 ACP33 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT IFNa- AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrr fusion lsplsclkdrkdfgfpqekvdaqqildcaqaipvlseltqqilniftskdssaawnttlldsfendlhqqlndlqgclmqqvg protein vqefpltqedallavrkythritvylrekkhspcawevvraevwralsssanvSGGPGPAGMKGLPGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS GRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQ GTLVTVSSHHHHHHEPEA 169 ACP131 mdmrvpaqllglllwlrgarcallpqthnlinkralfilvqmrrlsplsclkdrkcifgfpqekvdaqqildcaqaipvlsel Mouse tqqilniftskdssaawnttlldsfendlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrekkhspcawe IFNa vvraevwralsssanvlgrlreekHHHHHHEPEA 170 ACP125 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT IFNa- AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGScdlpqthnlrnkraltllvqmrr fusion lsplsclkdrkdfgfpqekvdaqqikkactaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvg protein vqefpltqedallavrIcyfhritvylrekkhspcawevvraevwralsssamIgrlreekHHHHHHEPEA 171 ACP126 mdmrvpaqllginiwlrgarccdlpqthnlrnkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkaqaipvlel Mouse tqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrIcyfhritvylrekkhspcawe IFNa- vvraevwralsssamIgrlreekSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSC fusion AASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNA protein KTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 172 ACP127 mdmrvpaqllglllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDE Mouse HAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADC IFNa- CTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVA fusion RRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQ protein RMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCH GDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMP ADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAK KYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGF QNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAI LNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFH SDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAA DKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGScdlpqthnlinkraltllvqmrrls plsclkdrkcifgfpqekvdaqqikkactaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgv qefpltqedallavrIcythritvylrekkhspcawevvraevwralsssamIgrlreekSGGPGPAGMKGLP GSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFA KTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFL QHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLY YAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGE RAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAEL AKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVED QEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEA NPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAP QVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPV SEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIK KQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNL VTRCKDALAHHHHHHEPEA 173 ACP128 mdmrvpaqllglllwlrgarcEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDE Mouse HAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADC IFNa- CTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVA fusion RRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQ protein RMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCH GDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMP ADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAK KYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGF QNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAI LNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFH SDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAA DKDTCFSTEGPNLVTRCKDALASGGPGPAGMKGLPGScdlpqthnlinkraltllvqmrrls plsclkdrkcifgfpqekvdaqqikkactaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgv qefpltqedallavrIcythritvylrekkhspcawevvraevwralsssamIgrlreekHHHHHHEPEA 174 ACP129 mdmrvpaqllglllwlrgarccdlpqtlmlmkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqikkactaipvlsel Mouse tqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrIcyfhritvylrekkhspcawe IFNa- vvraevwralsssamIgrlreekSGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGL fusion VLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKL protein CAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSF KENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTP KLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVARLSQTFPNADFAEIT KLATDLTKVNKECCHGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLL KKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEAKDVFLGTFLYEYSR RHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVK TNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLP EDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDE TYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVM DDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAHHHHHHEPEA 175 ACP150 mdmrvpaqllglllwlrgarcQVQLQESGGGLAQAGGSLSLSCAASGFTVSNSVMAWY Mouse RQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMNNLKPEDT IFNa- AVYVCNRNFDRIYWGQGTQVTVSSggggsggggsggggsEVQLVESGGGLVQPGNS fusion LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI protein SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAG MKGLPGScdlpqthnlinkraltllvqmrrlsplsclkdrkclfgfpqekvdaqqikkapipvlseltqqilniftskd ssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkythritvylrekichspcawevvraevwral sssanylgrlreekSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTF SKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYL QMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHHEPEA 176 ACP151 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT IFNa- AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGScdlpqthnlinkraltllvqmrr fusion lsplsclkdrkdfgfpqekvdaqqikkaqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvg protein vqefpltqedallavrkyfhritvylrekkhspcawevvraevwralsssanylgrlreekSGGPGPAGMKGLP GSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSS ISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSV SSQGTLVTVSSggggsggggsggggsQVQLQESGGGLAQAGGSLSLSCAASGFTVSN SVMAWYRQTPGKQREFVAIINSVGSTNYADSVKGRFTISRDNAKNTVYLQMN NLKPEDTAVYVCNRNFDRIYWGQGTQVTVSSHHHHHHEPEA 177 ACP152 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR Mouse QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT IFNa- AVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggscdlpqthnlinkraltllvqmrrlsplscl fusion kdrkdfgfpqekvdaqqikkacjaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpl protein tqedallavrkyfhritvylrekkhspcawevvraevwralsssanylgrlreekggggsggggsggggsEVQLVE SGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSHHHHHHEPEA 178 ACP153 mdmrvpaqllglllwlrgarcaptsssildctqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle (WW0201) eelkpleevinlaqsknfhlrprdlisninvivlelkgsetifmceyadetativeflnrwitfcqsiistltsgGPAGL (IL-2 YAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLE Conju- WVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIG gate) GSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEV QLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSS YTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDY WGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAS QNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 179 ACP154 mdmrvpaqllglllwlrgarcaptsssildctqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcle (WW0202) eelkpleevinlaqsknfhlrprdlisninvivlelkgsetifmceyadetativeflnrwitfcqsiistltsggpPGGPA (IL-2 GIGpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEW Conju-g VSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGS ate) LSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpPGGPAGIGpgsEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVG TNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFA TYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 180 ACP155 mdmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmilfkfympkkatelkhlqcle (WW0203) eelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSS (IL-2 FPpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWV Conju- SSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSL gate) SVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVE SGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYS PDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQG TTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGT NVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 181 ACP156 mdmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmilfkfympkkatelkhlqcle (WW0204) eelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpPLAQK (IL-2 LKSSpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLE Conju- WVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIG gate) GSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpPLAQKLKSSpgsEV QLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSS YTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDY WGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAS QNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHHEPEA 182 ACP157 mdmrvpaqllglllwlrgarcaptssstkktqlqlehllldlqmilnginnyknpkltrmilfkfympkkatelkhlqcle (WW0205) eelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpPGGPA (IL-2 GIGalfkssfpPLAQKLKSSpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGM Conju- SWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSL gate) RPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggp PGGPAGIGalfkssfpPLAQKLKSSpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASF RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK HHHHHHEPEA 183 Not assigned 184 Not assigned 185 Not assigned 186 Not assigned 187 Not assigned 188 Not assigned 189 Not assigned 190 Not assigned 191 Blocker 2 mdmrvpaqllglllwlrgarcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVR (IL2 QAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTA blocker) VYYCARDSNWDALDYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASV GDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSG TDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH mdmrvpaqllglllwlrgarcQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQ 192 Blocker 12 (IL-12 LPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSY blocker) DRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSC AASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDN SKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 193 Human IF cdlpqthslgsrrtlmllaqmrrislfsclkdrhdfgfpqeefgnqfqkaetipvlhemiqqifhlfstkdssaawdetlldk NA2b fytelyqqlndleacviqgvgvtetplmkedsilavrkyfqritlylkekkyspcawevvraeimrsfslstnlqesliske HHHHHH** 194 ACP239- iwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshs geneart llllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt wstphsyfshfcvqvqgkskrekkdwftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsggggsr vipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgs clppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgead pyrvkmklcillhafstrvvtinrvmgylssahhhhhh 195 3CYT5_sd QVQLQESGGGLVQAGGSLRLSCAASGRTFSSVYDMGWFRQAPGKDREFVARI AbTESARNTRYADSVRGRFTISRDNAKNTVYLQMNNLELEDAAVYYCAADPQT VVVGTPDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 196 ACP248 QSVLTQPPSVSGAPGQRVTISCtGSsSNIGSNTVKWYQQLPGTAPKLLIYgNDQR PSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPAyvFGTGTKVT VLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQ APGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT AVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 197 ACP249 QSVLTQPPSVSGAPGQRVTISCtGSsSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPAyvFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 198 ACP250 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYaMHWV RQAPGKGLEWVAvIsYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCarHGSHDNWGQGTMVTVSSHHHHHH 199 ACP251 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYeGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 200 ACP252 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYAeSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 201 ACP253 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSqTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYeRYTHPALLFGTGTKV TVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR QAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 202 ACP254 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSqTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYsRYTHPALLFGTGTKV TVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR QAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 203 ACP255 QSVLTQPPSVSGAPGQRVTISCSGSeSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 204 ACP256 QSVLTQPPSVSGAPGQRVTISCSGSsSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 205 ACP257 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGdNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 206 ACP258 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGeNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 207 ACP259 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSdTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 208 ACP260 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSeTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 209 ACP261 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNdVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 210 ACP262 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVdWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 211 ACP263 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVeWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 212 ACP264 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ dPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 213 ACP265 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ ePSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 214 ACP266 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPdGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 215 ACP267 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDeYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 216 ACP268 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTdPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 217 ACP269 QSVLTQPPSVSGAPGQRVTISCSGSeSNIGSNTVKWYQQLPGTAPKLLIYYNDQ ePSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDeYTHPALLFGTGTKV TVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVR QAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 218 ACP270 QSVLTQPPSVSGAPGQRVTISCSGSeSNIGSNdVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 219 ACP271 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFeSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 220 ACP272 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSeYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 221 ACP273 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSdYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 222 ACP274 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIeYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 223 ACP275 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIdYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 224 ACP276 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNdYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 225 ACP277 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNeYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 226 ACP278 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVeGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 227 ACP279 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSeDNWGQGTMVTVSSHHHHHH 228 ACP280 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIeYDGSNKYYADSVeGRFTISRDNSKNTLYLQMNSLRAED TAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 229 ACP281 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIeYDGSNKYYADSVeGRFTISRDNSKNTLYLQMNSLRAED TAVYYCKTHGSeDNWGQGTMVTVSSHHHHHH 230 ACP282 QSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQ RPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLFGTGTK VTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV RQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH 231 ACP283 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwddqssevlgsgktltiqvkefgdagqytchkggevlshs (WW0617) sgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgdllllhkkedgiwstdilkdqkepknktflrceakny nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt wstphsyfshfcvqvqgkskrekkdrvftdktsatvicrknasisvraqMyyssswsewasvpcs 232 3TOW69sd QVQLQESGGGLVQTGGSLRLSCTTSGTIFSGYTMGWYRQAPGEQRELVAVISG Ab GGDTNYADSVKGRFTISRDNTKDTMYLQMNSLKPEDTAVYYCYSREVTPPW KLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 233 3TOW85sd QVQLQESGGGLVQEGGSLRLSCAASERIFSTDVMGWYRQAAEKQRELVAVVS Ab ARGTTNYLDAVKGRFTISRDNARNTLTLQMNDLKPEDTASYYCYVRETTSPW RIYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 234 2T0W91sd QVQLQESGGGLVQAGGSLRLSCAASGSlFSANAMGWYRQAPGKQRELVAVIS Ab SGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCMYSGSYYY TPNDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 235 ACP301 evqlvesggglvqpggslrlscaasgftfssytlawvrqapgkglewvaaidsssytyspdtvrgrftisrdnaknslylq mnslraedtavyycardsnwdaldywgqgttvtvssggggsggggsggggsdiqmtqspsslsasvgdrvtitckasq nvgtnvgwyqqkpgkapkaliysasflysgvpsrfsgsgsgtdftltisslqpecifatyycqqyytypylfgggtkveik hhhhhh 236 Hu2TOW9 evqllesggglvqpggslrlscaasGSIFSANAMGwYrqapgkQReLvAVISSGGSTNYADSVK 1_A GrftisrdnskntVylqmnslraedtavyycMYSGSYYYTPNDYwgqgtivtvssAAAYPYDVPD YGSHHHHHH** 237 Hu2TOW9 evqllesggglvqpggslrlscaasGSIFSANAMGwYrqapgkgleLvAVISSGGSTNYADSVKG 1_B rftisrdnskntVylqmnslraedtavyycMYSGSYYYTPNDYwgqgtivtvssAAAYPYDVPDY GSHHHHHH** 238 Hu2TOW9 evqllesggglvqpggslrlscaasGSIFSANAMGwvrqapgkglewvsVISSGGSTNYADSVKGrf 1_C tisrdnskntlylqmnslraedtavyycMYSGSYYYTPNDYwgqgtivtvssAAAYPYDVPDYGS HHHHHH** 239 Hu2TOW9 QvqllesggglvqpggslrlscaasGSIFSANAMGwYrqapgkQReLvAVISSGGSTNYADSVK 1_D GrftisrdnskntVylqmnslraedtavyycMYSGSYYYTPNDYwgqgtivtvssAAAYPYDVPD YGSHHHHHH** 240 HE_LM_2 evqllesggglvqpggslrlscaasgSIfsANamGwYrqapgkgReLvAVissggstNyadsvkgrftisrdns TOW91 kntVylqmnslraedtavyycMYSGSYYYTPNDYWgqgtivtvssAAAYPYDVPDYGSHHH HHH** 241 HE_LM_2T QvqllesggglvqAggslrlscaasgSIfsANamGwYrqapgkQReLvAVissggstNyadsvkgrftisrdn OW91 skntVylqmnslraedtavyycMYSGSYYYTPNDYwgqgtivtvssAAAYPYDVPDYGSHHH HHH** 242 Hu3TOW8 evqllesggglvqpggslrlscaasERIFSTDVMGwYrqapgkQReLvAVVSARGTTNYLDAV 5_A KGrftisrdnskntlylqmnslraedtavyycYVRETTSPWRIYwgqgtivtvssAAAYPYDVPDYG SHHHHHH** 243 Hu3TOW8 evqllesggglvqpggslrlscaasERIFSTDVMGwYrqapgkgleLvAVVSARGTTNYLDAVK 5_B GrftisrdnskntlylqmnslraedtavyycYVRETTSPWRIYwgqgtivtvssAAAYPYDVPDYGS HHHHHH** 244 Hu3TOW8 evqllesggglvqpggslrlscaasERIFSTDVMGwvrqapgkglewvsVVSARGTTNYLDAVKG 5_C rftisrdnskntlylqmnslraedtavyycYVRETTSPWRIYwgqgtivtvssAAAYPYDVPDYGSH HHHHH** 245 Hu3TOW8 QvqllesggglvqpggslrlscaasERIFSTDVMGwYrqapgkQReLvAVVSARGTTNYLDAV 5_D KGrftisrdnskntlylqmnslraedtavyycYVRETTSPWRIYwgqgtivtvssAAAYPYDVPDYG SHHHHHH** 246 HE_LM_3 evqllesggglvqpggslrlscaasERIfsTDVmGwYrqapgkgReLvAVVsARgTtNyLdsvkgrftisr TO1T85 dnskntlylqmnslraedtavyycYVRETTSPWRIywgqgtivtvssAAAYPYDVPDYGSHHHH HH** 247 HE_L_3T QvqllesggglvqEggslrlscaasERIfsTDVmGwYrqaAgkQReLvAVVsARgTtNyLdAvkgrf OW85 tisrdnskntlylqmnslraedtaSyycYVRETTSPWRIywgqgtivtvssAAAYPYDVPDYGSHH HHHH** 248 HE_LM_R evqllesggglvqpggslrlscaasERIfsTDVmGwYrqapgkgleLvAVVsARgTtNyLdsvkgrftisr 45L_3TO dnskntlylqmnslraedtavyycYVRETTSPWRIywgqgtivtvssAAAYPYDVPDYGSHHHH W85 HH** 249 Hu3TOW6 evqllesggglvqpggslrlscaTsGTIFSGYTMGwYrqapgkQReLvAVISGGGDTNYADSV 9_A KGrftisrdnskDtMylqmnslraedtavyycYSREVTPPWKLYwgqgtivtvssAAAYPYDVPD YGSHHHHHH** 250 Hu3TOW6 evqllesggglvqpggslrlscaTsGTIFSGYTMGwYrqapgkgleLvAVISGGGDTNYADSVK 9_B GrftisrdnskDtMylqmnslraedtavyycYSREVTPPWKLYwgqgtivtvssAAAYPYDVPDY GSHHHHHH** 251 Hu3TOW6 evqllesggglvqpggslrlscaasGTIFSGYTMGwvrqapgkglewvsVISGGGDTNYADSVKGr 9_C ftisrdnskntlylqmnslraedtavyycYSREVTPPWKLYwgqgtivtvssAAAYPYDVPDYGSH HHHHH** 252 Hu3TOW6 QvqllesggglvqpggslrlscaTsGTIFSGYTMGwYrqapgkQReLvAVISGGGDTNYADSV 9_D KGrftisrdnskDtMylqmnslraedtavyycYSREVTPPWKLYwgqgtivtvssAAAYPYDVPD YGSHHHHHH** 253 Hu3TOW6 evqllesggglvqpggslrlscaTsGTIFSGYTMGwYrqapgkQReLvAVISGGGDTNYADSV 9_E KGrftisrdnskntMylqmnslraedtavyycYSREVTPPWKLYwgqgtivtvssAAAYPYDVPD YGSHHHHHH** 254 HE_LM_3 evqllesggglvqpggslrlscaTsgTIfsGyTmGwYrqapgkgReLvAVisGggDtNyadsvkgrftisrd TO1T69 nskntMylqmnslraedtavyycYSREVTPPWKLywgqgtivtvssAAAYPYDVPDYGSHHH HHH** 255 HE_L_3T QvqllesggglvqTggslrlscaTsgTIfsGyTmGwYrqapgkQReLvAVisGggDtNyadsvkgrftisr OW69 dnskDtMylqmnslraedtavyycYSREVTPPWKLywgqgtivtvssAAAYPYDVPDYGSHH HHHH** 256 HE_LM_R evqllesggglvqpggslrlscaTsgTIfsGyTmGwYrqapgkgleLvAVisGggDtNyadsvkgrftisrdn 45L_3TO skntMylqmnslraedtavyycYSREVTPPWKLywgqgtivtvssAAAYPYDVPDYGSHHHH W69 HH** 257 ACP363 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0441) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKAREKL WSAVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 258 ACP364 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0442) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKAREKL WSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 259 ACP367 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0445) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKVTEKV WGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 260 ACP369 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0449) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKSSEKL WANVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPED FATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 261 ACP370 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0450) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKSSEKL WANVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 262 ACP380 DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASF (WW0522) RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvellnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgec 263 ACP381 DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASF (WW0523) RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvellnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgec 264 ACP382 DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSL (WW0524) RKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvellnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgec 265 ACP435 DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASF RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvellnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlsca asgsifsanamgwyrqapgkrirelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsy yytpndywgqgtivtvss** 266 ACP436 DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASF (WW0578) RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvellnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlsca asgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsy yytpndywgqgtivtvss** 267 ACP437 DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSL (WW0579) RKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvellnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlsca asgsifsanamgwyrqapglairelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsy yytpndywgqgtivtvss** 268 ACP438 DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSL (WW0580) RKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvellnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlsca asgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsy yytpndywgqgtivtvss** 269 ACP448 DIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKsLIYSASF (WW0590) RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgec** 270 ACP449 DIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPGKAPKLLIYSASF (WW0591) RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgec** 271 ACP450 DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKLLIYSASF (WW0592) RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgec** 272 ACP439 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0581) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPG KAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYP YTFGGGTKVEIK 273 ACP440 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0582) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPG KAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIK 274 ACP441 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0583) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPG KAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIK 275 ACP442 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0584) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPG KAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGcGTKVEIK 276 ACP443 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0585) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPG KAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGcGTKVEIK 277 ACP444 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0586)dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKSSEKLWANVAWYQQKPG KcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIK 278 ACP445 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0587) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpG PAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKA PKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTF GGGTKVEIK 279 ACP446 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0588) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIK 280 ACP447 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0589) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGcGTKVEIK 281 ACP451 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0615) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltsggpALFKSSFPpgsEVQLVESGGG LVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAES VKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgg ggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRL SCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSG GGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKA PKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTF GGGTKVEIK** 282 ACP452 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0616) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGG LVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAES VKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgg ggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRL SCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSG GGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGK APISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTF GGGTKVEIK** 283 ACP453 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0617) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGG LVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAES VKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgg ggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRL SCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNA KNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGG GGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAP KsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFG cGTKVEIK** 284 ACP454 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0618) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGG LVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAES VKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgg ggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRL SCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSG GGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKc PKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTF GGGTKVEIK** 285 ACP455 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGG (WW0619) LVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAES VKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgg ggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRL SCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNA KNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGG GGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKA PISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFG cGTKVEIK** 441 ACP456 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGG (WW0620) LVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAES VKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgg ggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRL SCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSG GGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKc PISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFG GGTKVEIK** 286 ACP457 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0621) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpALFKSSFPpgsEVQLVESGGG LVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAES VKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSgg ggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRL SCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfp lapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsnt kvdkrvepksc** 287 ACP458 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0622) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp ALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympkkatelkhlqcleeelkplee vinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggg gsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclv kdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc** 288 ACP459 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0623) qfnstyrvvsyltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp ALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympkkatelkhlqcleeelkplee vinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggg gsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRY SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 289 ACP460 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0624) qfnstyrvvsyltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp ALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympkkatelkhlqcleeelkplee vinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggg gsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRK SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 290 ACP461 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0625) qfnstyrvvsyltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp ALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympkkatelkhlqcleeelkplee vinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggg gsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSL RAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQ MTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 291 ACP462 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0626) qfnstyrvvsyltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp ALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympkkatelkhlqcleeelkplee vinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggg gsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQ MTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 292 ACP463 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0627) qfnstyrvvsyltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp ALFKSSFPpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympkkatelkhlqcleeelkplee vinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggg gsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSL RAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQ MTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 293 ACP464 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcyvvdvsqedpevqfnwyydgvevhnaktkpree (WW0628) qfnstyrvvsyltvlhqdwingkeykcicvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp ALFKSSFPpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmlfficfympkkatelkhlqcleeelkplee vinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggg gsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSY TLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQ MTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 294 ACP465 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcyvvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0629) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpAL FKSSFPpgsaptsssticktqlqlehllldlqmilnginnyknpklbnillfldympkkatelkhlqcleeelkpleevin laqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggsg gggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTL AWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQM TQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 295 ACP466 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcyvvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0630) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpAL FKSSFPpgsaptsssticktqlqlehllldlqmilnginnyknpklbnillfldympkkatelkhlqcleeelkpleevin laqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggsg gggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTL AWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQM TQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 296 ACP467 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcyvvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0631) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpAL FKSSFPpgsaptsssticktqlqlehllldlqmilnginnyknpklbnillfldympkkatelkhlqcleeelkpleevin laqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggsg gggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTL AWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQM TQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 297 ACP468 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcyvvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0632) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpAL FKSSFPpgsaptsssticktqlqlehllldlqmilnginnyknpklbnillfldympkkatelkhlqcleeelkpleevin laqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggsg gggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTL AWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 298 ACP469 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcyvvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0633) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpAL FKSSFPpgsaptssstkktqlqlehllldlqmilngiimyknpklliiiiltfkfympkkatelkhlqcleeelkpleevin laqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggsg gggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTL AWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQM TQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 299 ACP470 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcyvvdiskddpevqfswfvddvevhtaqtqpreeqfnslf (WW0634) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpAL FKSSFPpgsaptsssticktqlqlehllldlqmilnginnyknpklbnillfldympkkatelkhlqcleeelkpleevin laqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggsg gggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTL AWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 300 ACP471 mdmrvpaqllglllwlrgarcvprdcgckpcictvpevssvfifppkpkdvltitltpkvtcvvvdiskddpevqfswf (WW0642) vddveyhtaqtqpreeqfnslfrsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeq makdkvsltcmitdffpeditvewqwngqpaenykntqpimdtdgsyfvysklnvqknweagntftcsvlheglh nhhtekslshspgksggpALFKSSFPpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmllfldympk katelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltg gggsggggsggggsggggsggggsggggssggpALFKSSFPpgsEVQLVESGGGLVQPGGSLR LSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRD NAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsv fplapsskstsggtaalgclykdyfpepvtvswnsgaltsgvhtipavlqssglyslssvvtvpssslgtqtyicnvnhkps nticvdkrvepksc** 301 ACP382 DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSL (WW0524) RKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvcllnaypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfnrgec** 302 ACP383 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcyvvdvsqedpevqfnwyydgvevhnaktkpree (WW0525) qfnstyrvvsyltvlhqdwingkeykcicvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmllfklympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASF RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK* * 303 ACP384 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcyvvdvsqedpevqfnwyydgvevhnaktkpree (WW0526) qfnstyrvvsyltvlhqdwingkeykcicvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSD IQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKcPKALIYSASFR YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 304 ACP385 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcyvvdvsqedpevqfnwyydgvevhnaktkpree (WW0527) qfnstyrvvsyltvlhqdwingkeykcicvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmllfklympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKALIYSASF RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK* * 305 ACP386 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0528) qfnstyrvvsyltvlhqdwingkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptssstIcktqlqlehllldlqmilnginnyknpkltrmltfkfympldcatelkhlqcleeelkpl eevinlaqsknfldrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSD IQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFR YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 306 ACP387 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0529) qfnstyrvvsyltvlhqdwingkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptssstIcktqlqlehllldlqmilnginnyknpkltrmltfkfympldcatelkhlqcleeelkpl eevinlaqsknfldrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSL RKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK* * 307 ACP388 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0530) qfnstyrvvsyltvlhqdwingkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptssstIcktqlqlehllldlqmilnginnyknpkltrmlfficfympldcatelkhlqcleeelkpl eevinlaqsknfldrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSD IQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRK SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 308 ACP389 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0531) qfnstyrvvsyltvlhqdwingkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptssstIcktqlqlehllldlqmilnginnyknpkltrmltfkfympldcatelkhlqcleeelkpl eevinlaqsknfldrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqr elvavissggstnyadsvkgrftisrdnskntvylqmnstraedtavyycmysgsyyytpndywgqgtivtvss** 309 ACP390 aptssstIcktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0532) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGcGTKVEIK** 310 ACP391 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0533) qfnstyrvvsyltvlhqdwingkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmlfficfympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistliggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASF RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK* * 311 ACP392 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0534) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqc qctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgy ralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtncifqiqtemaatmetsiftt eyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGD RVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 312 ACP393 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0535) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqc qctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgy ralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtncifqiqtemaatmetsiftt eyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDR VTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDF TLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 313 ACP394 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0536) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqc qctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgy ralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtncifqiqtemaatmetsiftt eyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGD RVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 314 ACP395 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0537) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqc qctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgy ralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtncifqiqtemaatmetsiftt eyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDR VTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 315 ACP396 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0538) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqc qctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgy ralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlytttclfqiqtemaatmetsiftt eyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisr dnskntvylqmnslraedtavyycmysgsyyytpndywgqgtivtvss** 316 ACP397 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0539) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqc qctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgy ralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlytttclfqiqtemaatmetsiftt eyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisr dnskntvylqmnslraedtavyycmysgsyyytpndywgqgtivtvss** 317 ACP398 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0540) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqc qctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgy ralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlytttclfqiqtemaatmetsiftt eyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgv htfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc** 318 ACP399 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDS SSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALD YWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKA REKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQ PEDFATYYCQQYYTYPYTFGcGTKVEIKsggpGPAGLYAQpgsggggsggggsggggsg gggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYY CTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsfficlympkkatelkhlqcleeelkpleevinl aqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltGGssstldctqlqle hllldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFS KFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQ MNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 319 ACP400 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKA REKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQ PEDFATYYCQQYYTYPYTFGGGTKVEIKsggpGPAGLYAQpgsggggsggggsggggsg gggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYY CTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsfficlympkkatelkhlqcleeelkpleevinl aqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltGGssstldctqlq lehllldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFS KFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQ MNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 320 ACP401 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDS SSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALD YWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKV TEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQ PEDFATYYCQQYYTYPYTFGcGTKVEIKsggpGPAGLYAQpgsggggsggggsggggsg gggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYY CTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsdklympkkatelkhlqcleeelkpleevinl aqsknfhlrprdlisninvivlelkgsetifmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehll ldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFS KFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQ MNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 321 ACP402 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKV TEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQYYTYPYTFGGGTKVEIKsggpGPAGLYAQpgsggggsggggsggggsgg ggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGK GLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYC TIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgstfklympkkatelkhlqcleeelkpleevinla qsknfldrprdlisninvivlelkgsellfmceyadetativeflnrwitfcqsiistltGGssstkktqlqlehlll dlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFS KFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQ MNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 322 ACP403 evqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvyl qmnslraedtavyycmysgsyyytpndywgqgtivtvsssggpGPAGLYAQpgsggggsggggsggggsg gggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYY CTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsdklympkkatelkhlqcleeelkpleevinl aqsknfhlrprdlisninvivlelkgsetifmceyadetativeflnrwideqsiistltGGssstkktqlqlehllldlqmiln ginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFS KFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQ MNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 323 ACP404 evqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvyl qmnslraedtavyycmysgsyyytpndywgqgtivtvsssggpGPAGLYAQpgsggggsggggsggggsg gggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYY CTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgsdklympkkatelkhlqcleeelkpleevinl aqsknfhlrprdlisninvivlelkgsetifmceyadetativeflnrwideqsiistltGGssstkktqlqlehllldlqmiln ginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFS KFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQ MNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 324 ACP405 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqss glyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepkscsggpGPAGLYAQpgsggggsggggsggggs ggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAP GKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVY YCTIGGSLSVSSQGTLVTVSSsggpGPAGLYAQpgstildympkkatelkhlqcleeelkpleevl nlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlq lehllldlqmilnginnyknpkltrmlsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTF SKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYL QMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 325 ACP406 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcwvdiskddpevqfswfvddvevhtaqtqpreeqfnstf (WW0548) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditv ewqwngqpaenykntqpimdtdgsyfyysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpGP AGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmifficfympkkatelkhlqcleeelkpleev lnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggs ggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYT LAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSL RAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaalgclvk dyfpepvtvswnsgaltsgvhdpavlqssglyslssvvtvpssslgtqtyicnvnhkpsnticvdlavepksc** 326 ACP407 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcwvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0549) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfyysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpGP AGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmifficfympkkatelkhlqcleeelkpleev lnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggs ggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYT LAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQM TQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKALIYSASFRYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 327 ACP408 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcwvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0550) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfyysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpGP AGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmifficfympkkatelkhlqcleeelkpleev lnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggs ggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYT LAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQM TQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 328 ACP409 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcwvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0551) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfyysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpGP AGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmifficfympkkatelkhlqcleeelkpleev lnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggs ggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYT LAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSL RAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQ MTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 329 ACP410 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcwvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0552) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfyysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpGP AGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmifficfympkkatelkhlqcleeelkpleev lnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggs ggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYT LAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLR AEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQM TQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIK** 330 ACP411 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcwvdiskddpevqfswfvddvevhtaqtqpreeqfnsif (WW0553) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitcapeditv ewqwngqpaenykntqpimdtdgsyfyysklnvqksnweagniftcsvlheglhnhhtekslshspgksggpGP AGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmifficfympkkatelkhlqcleeelkpleev lnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwilfcqsiistltggggsggggsggggsggggs ggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYT LAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSL RAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQ MTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 331 ACP412 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcwvdiskddpevqfswfvddvevhtaqtqpreeqfnstf (WW0554) rsyselpimhqdwhigkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitclffpeditv ewqwngqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgksggpGP AGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmlafympkkatelkhlqcleeelkpleev lnlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltggggsggggsggggsggggs ggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelv avissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtivtvss** 332 ACP413 elcdddppeiphafficamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpee (WW0555) qkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgk trwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttclfqiqtemaatmetsiftteyqggggsggggsgggg sggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd styslsstifiskadyekhkvyacevthqglsspvtksfnrgec** 333 ACP414 elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpee (WW0556) qkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgk trwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttclfqiqtemaatmetsiftteyqggggsggggsgggg sggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKP GKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYP YTFGGGTKVEIKrtvaapsvfifppsdeqlksgtasvvcllnaypreakvqwkvdnalqsgnsqesvteqds kdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec** 334 ACP415 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0557) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQA PGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVY YCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLS ASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsgg ggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctg nsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgq mvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvMdfqiqte maatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFS KFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQ MNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 335 ACP416 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0558) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQA PGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVY YCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSA SVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFRYSGVPSRFSGSG SGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsggg gsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgns shsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqm vyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttdfqiqtem aatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSK FGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQM NSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 336 ACP417 aptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0559) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQA PGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVY YCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLS ASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKggggsggggsggggsgg ggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctg nsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgq mvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvMdfqiqte maatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFS KFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQ MNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 337 ACP418 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0560) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQA PGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVY YCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSA SVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRKSGVPSRFSGSGS GTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggggsggggsggggsgggg sggggsggggsggggsggggsggggselcdddppeiphatikamaykegtmlnceckrgfrriksgslymlctgnss hsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmv yyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtddfqiqtema atmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKF GMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMN SLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 338 ACP419 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0561) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkqrelvavissggstnyad svkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtivtvssggggsggggsggggsggg gsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgns shsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqm vyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtddfqiqtem aatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSK FGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQM NSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 339 ACP420 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0562) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsggggsggggsggg gsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyad svkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtivtvssggggsggggsggggsggg gsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgns shsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqm vyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtddfqiqtem aatmetsiftteyqsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSK FGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQM NSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 340 ACP421 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (WW0563) GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASF RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKg gggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlncec krgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepp pweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspeg rpesetsSlvtddfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLY AQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmlafympkkatelkhlqcleeelkpleevinlaqsk nfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitieqsiistlt** 341 ACP422 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (WW0564) GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSD IQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKcPKALIYSASFR YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKgg ggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceck rgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcreppp weneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegr pesetsSlytttclfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYA Qpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmlfficfympkkatelkhlqcleeelkpleevinlaqsknf hlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistlt** 342 ACP423 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (WW0565) GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSL RKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGcGTKVEIKg gggsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlncec krgfrriksgslymktgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepp pweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspeg rpesetsSlvMdfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLY AQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsk nfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistlt** 343 ACP424 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (WW0566) GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGGSGGGGSGGGGSD IQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKcPISLIYSPSLRK SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKggg gsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatikamaykegtmlnceckr gfrriksgslymktgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppw eneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpe setsSlytttclfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQ pgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympldcatelkhlqcleeelkpleevinlaqsknfh lrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistlt** 344 ACP425 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (WW0567) GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkq relvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtivtvssggg gsggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatikamaykegtmlnceckr gfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppw eneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpe setsSlytttclfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQ pgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympldcatelkhlqcleeelkpleevinlaqsknfh lrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistlt** 345 ACP426 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS (WW0568) GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkg lelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtivtvssgggg sggggsggggsggggsggggsggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgf rriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppwe neateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpes etsSlytttclfqiqtemaatmetsiftteyqggggsggggsggggsggggsggggsggggssggpGPAGLYAQp gsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlr prdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistlt** 346 ACP427 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0569) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGcGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsana mgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndyw gqgtivtvss** 347 ACP428 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0570) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsan amgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndy wgqgtivtvss** 348 ACP429 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0571) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKP GKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYP YTFGcGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsa namgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndy wgqgtivtvss** 349 ACP430 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0572) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKP GKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsan amgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndy wgqgtivtvss** 350 ACP431 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0573) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGcGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsana mgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndyw gqgtivtvss** 351 ACP432 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0574) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsan amgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndy wgqgtivtvss** 352 ACP433 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0575) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKP GKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYP YTFGcGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsa namgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndy wgqgtivtvss** 353 ACP434 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0576)dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKP GKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIKggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlscaasgsifsan amgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndy wgqgtivtvss** 265 ACP435 DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASF (WW0577) RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKr tvaapsvfifppsdeqlksgtasvvellnaypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekh kvyacevthqglsspvtksfmgecggggsggggsggggsggggsggggsggggsevqllesggglvqpggslrlsca asgsifsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsy yytpndywgqgtivtvss** 355 ACP371 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0513) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPG KAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYP YTFGcGTKVEIK** 356 ACP372 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0514) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPG KcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIK** 357 ACP373 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0515) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYP YTFGcGTKVEIK** 358 ACP374 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0516) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KcPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIK** 359 ACP375 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0517) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKcLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKP GKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYP YTFGcGTKVEIK** 360 ACP376 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0521) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGcGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKP GKcPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIK** 361 ACP377 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0519) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsi fsanamgwyrqapgkqrelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytp ndywgqgtivtvss** 362 ACP378 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0520) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgps vfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkp sntkvdkrvepksc** 363 ACP379 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0521) qfnstyrvvsyltvlhqdwingkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtlmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmlfficfympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSastkgpsvfplapsskstsggtaal gclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepksc** 364 ACP368 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0446)SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKVTE KVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 365 ACP365 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0443) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKARE KLWSAVAWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 366 ACP366 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0444) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKARE KLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH 367 ACP284 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGMKGLPGSwipvsgparclsquallkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslahngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAG MKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGS RSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGL QAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGG GVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMV TVSS 368 ACP285 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtl dqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrcealmysgrftcw wittistdilfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsaSpaaeeslpievmvdavhklkyeny tssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltkvqvqgkskrekkdrvftdktsatvicrkna sisvramthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsquallkttddmvktareklkhyscta edidheditrdqtstlktclplelhknesSlatretssttrgsclppqktslmmticlgsiyedllanyqtefgainaalqnhnh qqiildkgmlvaidelmqslahngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPA GMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCS GSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAIT GLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVES GGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGT MVTVSS 369 ACP286 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtl dqssevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrcealmysgrftcw wittistdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyeny tssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrkna sisvracichyyssswsewasvpcsggggsggggsggggsggggsrvipvsgparclsqsrffilkttddmvktareklk hysctaedidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefclainaal qnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGG PGPAGMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVT ISCSGSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSAS LAITGLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQ LVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDG SNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWG QGTMVTVSS 370 ACP287 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtl dqssevlgsgkiltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrcealmysgrftcw wittistditfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyeny tssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfslffevqvqgkskrekkdrvftdktsatvicrkna sisvracichyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsmllkttddmvktareklkhyscta edidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnh qqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPA GMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCS GSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAIT GLQAEDEADYYCQSYDRYTHPALLFGcGTKVTVLggggsggggsggggsQVQLVES GGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKcLEWVAFIRYDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTM VTVSS 371 ACP288 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtl dqssevlgsgkiltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrcealmysgrftcw wittistdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyeny tssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrkna sisvracichyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsmllkttddmvktareklkhyscta edidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnh qqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmkillhafstrvvtinrvmgylssaSGGPGPA GMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCS GSRSNIGSNTVKWYQQLPGTcPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAIT GLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVES GGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNK YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGcGT MVTVSS 372 ACP289 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0233) dlisninvivlelkgsettfmceyadetativeflnrwirdeqsiistltsggpgpagmkglpgsevqlvesggglvqpgns lrlscaasgftiskfgmswvrqapgkglewvssisgsgrdtlyaesvkgrftisrdnakttlylqmnslrpedtavyyctig gslsyssqgtivtvssggggsggggsggggsggggsggggsggggssggpgpagmkglpgsevqlvesggglvqpg gslrlscaasgftfssytlawvrqapgkglewvaaidsssytyspdtvrgrftisrdnaknslylqmnslraedtavyycar dsnwdaldywgqgttvtvssggggsggggsggggsdiqmtqspsslsasvgdrvtitckasqnvgtnvgwyqqkpg kapkaliysasfrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyytypyttggtkveikhhhhhh 373 ACP290 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0234) dlisninvivlelkgsettfmceyadetativeflnrwirdeqsiistltsggpgpagmkglpgsevqlvesggglvqpgns lrlscaasgftiskfgmswvrqapgkglewvssisgsgrdtlyaesvkgrftisrdnakttlylqmnslrpedtavyyctig gslsyssqgtivtvssggggsggggsggggsggggsggggsggggssggpgpagmkglpgQVQLQESGGG LVQTGGSLRLSCTTSGTIFSGYTMGWYRQAPGEQRELVAVISGGGDTNYADS VKGRFTISRDNTKDTMYLQMNSLKPEDTAVYYCYSREVTPPWKLYWGQGTQ VTVSSAAAYPYDVPDYGSHHHHHH 374 ACP291 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqskahlrpr (WW0235) dlisninvivlelkgsettfmceyadetativeflnrwitieqsiistltsggpgpagmkglpgsevqlvesggglvqpgns lrlscaasgitiskfgmswvrqapgkglewvssisgsgrdtlyaesvkgrftisrdnakttlylqmnslrpedtavyyctig gslsyssqgtivtvssggggsggggsggggsggggsggggsggggssggpgpagmkglpgQVQLQESGGG LVQEGGSLRLSCAASERIFSTDVMGWYRQAAEKQRELVAVVSARGTTNYLDA VKGRFTISRDNARNTLTLQMNDLKPEDTASYYCYVRETTSPWRIYWGQGTQV TVSSAAAYPYDVPDYGSHHHHHH 375 ACP292 aptssstkktqlqlehllldlqmilnginnyknpkltrmltildympldcatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0236) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltsggpgpagmkglpgsevqlvesggglvqpgns lrlscaasgfifskfgmswvrqapgkglewvssisgsgrdtlyaesvkgrftisrdnakttlylqmnslrpedtavyyctig gslsyssqgtivtvssggggsggggsggggsggggsggggsggggssggpgpagmkglpgQVQLQESGGG LVQAGGSLRLSCAASGSIFSANAMGWYRQAPGKQRELVAVISSGGSTNYADS VKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCMYSGSYYYTPNDYWGQGT QVTVSSAAAYPYDVPDYGSHHHHHH 376 ACP296 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0250) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltSGGPGPAGMKGLPGSEVQLVES GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLV QPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVS SSGGPGPAGMKGLPGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWY QQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YYTYPYTFGGGTKVEIKHHHHHHEPEA** 377 ACP297 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0251) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltSGGPGPAGMKGLPGSEVQLVES GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLV QPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWY QQKPGKAPKLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YYTYPYTFGGGTKVEIKHHHHHHEPEA** 378 ACP298 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0252) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltSGGPGPAGMKGLPGSEVQLVES GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLV QPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWY QQKPGKAPKGLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YYTYPYTFGGGTKVEIKHHHHHHEPEA** 379 ACP299 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0253) dlisninvivlelkgsettfmceyadetativeflnrwitiSqsiistltSGGPGPAGMKGLPGSEVQLVES GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLV QPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWY QQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YYTYPYTFGGGTKVEIKHHHHHHEPEA** 380 ACP300 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0255) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltSGGPGPAGMKGLPGSdahksevahrf kdlgeenfkalvliafaqylqqcpfedhvklvnevtefaktcvadesaencdkslhtlfgdklctvatlretygemadcca kqepernecflqhkddnpnlprlvrpevdvmctafhdneeffildcylyeiarrhpyfyapellffakrykaafteccqaa dkaacllpkldelrdegkassakqrlkcaslqkfgerafkawavarlsqrfpkaefaevsklvtdltkvhtecchgdlleca ddradlakyicenqdsissklkeccekpllekshciaevendempadlpslaacIfveskdvcknyaeakdvflgmfly eyarrhpdysvvlllrlaktyettlekccaaadphecyalcvfdefkplveepqnlikqncelfeqlgeykfqnallviyildc vpqvstptivevsralglcvgskcckhpeakrmpcaedylsvvinqlcvlhektpvsdrytkccteslvarrpcfsalevd etyvpkefnaaftfhadictlsekerqikkqtalvelvlchkpkatkeqlkavmddfaafvekcckaddketcfaeegldc lvaasqaalglggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGG GLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDT VRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTV TVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVG WYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQYYTYPYTFGGGTKVEIKHHHHHHEPEA** 381 ACP302 aptsssildctqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0296) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltSGGPGPAGMKGLPGSEAHKSEIA HRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAA NCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLP PFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILT QCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVA RLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQA TISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEA KDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVL AEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAA RNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGS LVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVK HKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAgg ggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPG KAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYP YTFGGGTKVEIKHHHHHH** 382 ACP303 EAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKT CVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQH KDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYA EQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERA FKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAK YMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQE VCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANP PACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQV STPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSE HVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKK QTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVT RCKDALASGGPGPAGMKGLPGSfficfympldcatelkhlqcleeelkpleevinlaqsknfhlrprdlis ninvivlelkgsettfmceyadetativeflnrwilfcqsiistltGGsssticktqlqlehllldlqmilnginnyknpkltrm ISGGPGPAGMKGLPGSEAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYD EHAKLVQEVTDFAKTCVADESAANCDKSLHTLFGDKLCAIPNLRENYGELAD CCTKQEPERNECFLQHKDDNPSLPPFERPEAEAMCTSFKENPFITMGHYLHEV ARRHPYFYAPELLYYAEQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVR QRMKCSSMQKFGERAFKAWAVARLSQlFPNADFAEITKLATDLTKVNKECC HGDLLECADDRAELAKYMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTM PADLPAIAADFVEDQEVCKNYAEAKDVFLGlFLYEYSRRHPDYSVSLLLRLAK KYEATLEKCCAEANPPACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGF QNAILVRYTQKAPQVSTPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAI LNRVCLLHEKTPVSEHVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFH SDICTLPEKEKQIKKQTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAA DKDTCFSTEGPNLVTRCKDALAHHHHHH** 383 ACP304 aptsssildctqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0302) dlisninvivlelkgsettfmceyadetativeflnrwiticqsiistltSGGPGPAGMKGLPGSEVQLVES GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLV QPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWY QQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSggggsggggsggggsggggsggggsggg gselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymktgnsshsswdnqcqctssatrnttkqvtpqp eeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvclunth gktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtltdfqiqtemaatmetsiftteyqHHHHHH** 384 ACP305 elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymktgnsshsswdnqcqctssatrnttkqvtpqpee (WW0303) qkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgk trwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyqggggsggggsgggg sggggsggggsggggsSGGPGPAGMKGLPGSaptssstlthqlqlehllldlqmilnginnyknpkltrmlIf kfympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfc qsiistltSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFG MSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNS LRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSG GPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQ APGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAV YYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSL SASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 385 ACP306 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0304) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggs ggggsggggsggggsggggselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymktgnsshsswd nqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcv qgyralhrgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmets iftteyqSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFG MSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNS LRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSG GPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQ APGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAV YYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSL SASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 386ACP307EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGMKGLPGSfficlympldcatelkhlqcleeelkpleevinlaqsknfhlrpr dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistitGGssstkktqlqlehllldlqmilnginnyknpkl trmlSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMS WVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLR PEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggsSGGP GPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAP GKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVY YCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLS ASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 387 ACP308 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCK ASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGMKGLPGSggggsggggsg gggsggggsggggsggggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT AVYYCTIGGSLSVSSQGTLVTVSSSGGPGPAGMKGLPGStfkfympkkatelkhlqcleee lkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltGGssstkktqlqle hllldlqmilnginnyknpkltrmlSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLS CAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDN AKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH** ACP309 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr 388 (WW0307) dlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVES GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLV QPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWY QQKPGKAPKSLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQY YTYPYTFGGGTKVEIKHHHHHH** 389 ACP310 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0308) dlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSEVQLVES GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSSggggsggggsggggsggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLV QPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWY QQKPGQAPRLLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQY YTYPYTFGGGTKVEIKHHHHHH** 390 ACP311 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0316) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSeskygppcpp cpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvl tvlhqdwingkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesn gqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgkggggsggggsggggs ggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASG FTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYS ASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHH** 391 ACP312 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0317) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennyklippvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgkSGG PGPAGMKGLPGSaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympkkatelkhlqcleeel kpleevinlaqsknfblrprdlisninvivlelkgsellfmceyadetativeflnrwitfcqsiistliggggsggggsgggg sggggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASG FTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYS ASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKV EIKHHHHHH** 392 ACP313 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0318) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltSGGPGPAGMKGLPGSggggsggggs ggggsggggsggggsggggsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVR QAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTA VYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPGPAGM KGLPGSeskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcwvdvsqedpevqfnwyvdgvevh naktkpreeqfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqv sliclvkgypsdiavewesngqpennyklippvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslsl slgIcHHHHHH** 393 ACP314 vprdcgckpcictypevssvfifppkpkdvltitltpkvtcwvdiskddpevqfswfvddvevhtaqtqpreeqfnslf (WW0354) rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitclffpeditv ewqwngqpaenykntqpimdtdgsyfyysklnvqksnweagnIftcsvlheglhnhhtekslshspgkSGGPG PAGMKGLPGSaptssstIcktqlqlehllldlqmilnginnyknpkltrmlffidympkkatelkhlqcleeelkple evinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwilfcqsiistltggggsggggsggggsgg ggsggggsggggsSGGPGPAGMKGLPGSEVQLVESGGGLVQPGGSLRLSCAASGFT FSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQ MNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSAS FRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEI KHHHHHH** 394 ACP336 aptssstIcktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0414) dlisninvivlelkgsetlfmceyadetativeflnrwilfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpG PAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKA PKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTF GGGTKVEIK** 395 ACP337 aptssstIcktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0415) dlisninvivlelkgsetlfmceyadetativeflnrwilfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPG KAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPY TFGGGTKVEIK** 396 ACP338 aptssstIcktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0416) dlisninvivlelkgsetlfmceyadetativeflnrwilfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpG PAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGK APISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTF GGGTKVEIK** 397 ACP339 aptssstIcktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0417) dlisninvivlelkgsetlfmceyadetativeflnrwilfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISR DNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGG SGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKP GKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYP YTFGGGTKVEIK** 398 ACP340 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0418) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsi fsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytp ndywgqgtivtvss** 399 ACP341 aptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrpr (WW0419) dlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistltsggpGPAGLYAQpgsEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaaseri fstdvmgwyrqapgkqrelvavvsargttnyldavkgrftisrdnskntlylqmnslraedtavyycyvrettspwriy wgqgtivtvss** 400 ACP342 elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpee (WW0420) qkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgk trwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtdclfqiqtemaatmetsiftteyqggggsggggsgggg sggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfy mpkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsii stltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVT ITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 401 ACP343 elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpee (WW0421) qkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgk trwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtdclfqiqtemaatmetsiftteyqggggsggggsgggg sggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfy mpkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsii stltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGD RVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 402 ACP344 elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpee (WW0422) qkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgk trwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtdclfqiqtemaatmetsiftteyqggggsggggsgggg sggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmilfkfy mpkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsii stltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVT ITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 403 ACP345 elcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqctssatrnttkqvtpqpee (WW0423) qkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgk trwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtdclfqiqtemaatmetsiftteyqggggsggggsgggg sggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfy mpkkatelkhlqcleeelkpleevinlaqsknfblrprdlisninvivlelkgsetlfmceyadetativeflnrwilleqsii stltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLE WVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARD SNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGD RVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 404 ACP346 elcdddppeiphatflcamaykegtmlnceckrgfrriksgslymktgnsshsswdnqcqctssatrnttkqvtpqpee (WW0424) qkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgk trwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttclfqiqtemaatmetsiftteyqggggsggggsgggg sggggsggggsggggssggpGPAGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmilflcfy mpkkatelkhlqcleeelkpleevinlaqsknfblrprdlisninvivlelkgsetlfmceyadetativeflnrwilleqsii stltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisr dnskntvylqmnslraedtavyycmysgsyyytpndywgqgtivtvss** 405 ACP347 elcdddppeiphatflcamaykegtmlnceckrgfrriksgslymktgnsshsswdnqcqctssatrnttkqvtpqpee (WW0425) qkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralhrgpaesvckmthgk trwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtttclfqiqtemaatmetsiftteyqggggsggggsgggg sggggsggggsggggssggpGPAGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmilflcfy mpkkatelkhlqcleeelkpleevinlaqsknfblrprdlisninvivlelkgsetlfmceyadetativeflnrwilleqsii stltsggpGPAGLYAQpgsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWV RQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPED TAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsggggsggggsggggsggggssggpGPAG LYAQpgsevqllesggglvqpggslrlscaaserifstdvmgwyrqapgkqrelvavvsargttnyldavkgrftisrd nskntlylqmnslraedtavyycyvrettspwriywgqgilvtvss** 406 ACP348 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0426) qfnstyrvvsyltvlhqdwhigkeykcicvsnkglpssiektiskakgqprepqvytlppsqeemilmqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistliggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQ MTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASFRYS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 407 ACP349 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0427) qfnstyrvvsyltvlhqdwhigkeykcicvsnkglpssiektiskakgqprepqvytlppsqeemilmqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmilfklympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistliggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKAREKLWSAVAWYQQKPGKAPKsLIYSASF RYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK ** 408 ACP350 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0428) qfnstyrvvsyltvlhqdwhigkeykcicvsnkglpssiektiskakgqprepqvytlppsqeemilmqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptsssticktqlqlehllldlqmilnginnyknpkltrmltfkfympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsetlfmceyadetativeflnrwitfcqsiistliggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSsggpGPAGLYAQpgsDIQ MTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSLRKS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK** 409 ACP351 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0429) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemilmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistliggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsEVQLVESGGGLVQPGGSLRLSCAASGFTFS SYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQM NSLRAEDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGS DIQMTQSPSSLSASVGDRVTITCKVTEKVWGNVAWYQQKPGKAPISLIYSPSL RKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIK ** 410 ACP352 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0430) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemilmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfklympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistliggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaasgsifsanamgwyrqapgkgl elvavissggstnyadsvkgrftisrdnskntvylqmnslraedtavyycmysgsyyytpndywgqgtivtvss** 411 ACP353 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0431) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemilmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgsaptssstkktqlqlehllldlqmilnginnyknpkltrmltfkfympldcatelkhlqcleeelkpl eevinlaqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfcqsiistliggggsggggsggggsgg ggsggggsggggssggpGPAGLYAQpgsevqllesggglvqpggslrlscaaserifstdvmgwyrqapgkqr elvavvsargttnyldavkgrftisrdnskntlylqmnslraedtavyycyvrettspwriywgqgtivtvss** 412 ACP354 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0432) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemilmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgselcdddppeiphalfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqcts satrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralh rgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtddfqiqtemaatmetsiftteyq ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilngin nyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfblrprdlisninvivlelkgsettfmceyadet ativeflnrwitfcqsiistliggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKAREKLWSA VAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCQQYYTYPYTFGGGTKVEIK** 413 ACP355 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0433) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemilmqvsltclvkgfy psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgselcdddppeiphalfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqcts satrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralh rgpaesvckmthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlvtddfqiqtemaatmetsiftteyq ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilngin nyknpkltrmltfkfympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadet ativeflnrwitfcqsiistliggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLW SAVAWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQYYTYPYTFGGGTKVEIK** 414 ACP356 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0434) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgselcdddppeiphalfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqcts satrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralh rgpaesvclunthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlytttdfqiqtemaatmetsiftteyq ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilngin nyknpkltrmlfficfympldcatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadet ativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKVTEKVWGN VAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYTYPYTFGGGTKVEIK** 415 ACP357 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0435) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgselcdddppeiphalfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqcts satrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralh rgpaesvclunthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlytttdfqiqtemaatmetsiftteyq ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilngin nyknpkltrmlfficfympkkatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadet ativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKV WGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYYTYPYTFGGGTKVEIK** 416 ACP358 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0436) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgselcdddppeiphalfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqcts satrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralh rgpaesvclunthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlytttdfqiqtemaatmetsiftteyq ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilngin nyknpkltrmlfficfympldcatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadet ativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesg gglvqpggslrlscaasgsifsanamgwyrqapgkglelvavissggstnyadsvkgrftisrdnskntvylqmnslrae dtavyycmysgsyyytpndywgqgtivtvss** 417 ACP359 eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree (WW0437) qfnstyrvvsyltvlhqdwhigkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfy psdiavewesngqpennykappvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgksggp GPAGLYAQpgselcdddppeiphatfkamaykegtmlnceckrgfrriksgslymlctgnsshsswdnqcqcts satrnttkqvtpqpeeqkerkttemqspmqpvdqaslpghcrepppweneateriyhfvvgqmvyyqcvqgyralh rgpaesvclunthgktrwtqpqlictgemetsqfpgeekpqaspegrpesetsSlytttdfqiqtemaatmetsiftteyq ggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsaptssstkktqlqlehllldlqmilngin nyknpkltrmlfficfympldcatelkhlqcleeelkpleevinlaqsknfhlrprdlisninvivlelkgsettfmceyadet ativeflnrwitfcqsiistltggggsggggsggggsggggsggggsggggssggpGPAGLYAQpgsevqllesg gglvqpggslrlscaaserifstdvmgwyrqapgkqrelvavvsargttnyldavkgrftisrdnskntlylqmnslraed tavyycyvrettspwriywgqgtivtvss** 418 ACP360 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0438) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSggggsggggsggggsDIQMTQSPSSLSASVGDRVTITCKASQNV GTNVGWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 419 ACP361 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0439) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKASQ NVGTNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 420 ACP362 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID (WW0440) SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSsggpGPAGLYAQpgsDIQMTQSPSSLSASVGDRVTITCKASQ NVGTNVGWYQQKPGKAPKsLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPE DFATYYCQQYYTYPYTFGGGTKVEIKHHHHHH** 421 ACP200 lveepknlyktncdlyeklgeygfqnailvlytqkapqvstptiveaarnlgrvgtkcctlpedqrlpcvedylsailnrycl lhektpvsehytkccsgslverrpcfsaltvdetyvpkefkaaftfhsdictlpekekqikkqtalaelvkhkpkataeqlk tvmdclfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGScdlpqthnlinkraltllyq mrrlsplsclkdrkclfgfpqekvdaqqikkaqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmq qvgvqefpltqedallavrkyfhrityylrelcichspcawevvraevwralsssanylgrlreekSGGPGPAGMK GLPGSlveepknlyktncdlyeklgeygfqnailvrytqkapqvstptiveaarnlgrvgtkcctlpedqrlpcvedyl sailnrycllhektpvsehytkccsgslverrpcfsaltvdetyvpkefkaelftihsdictlpekekqikkqtalaelvklikp kataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaHHHHHH** 422 ACP201 eahkseialuyndlgeqhfkglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlr enygeladcctkqepernecflqhkddnpslppferpeaeamctsfkenptlfmghylhevarrhpyfyapellyyaeq yneiltqccaeadkescltpkldgykekalvssvrqGGGGSGGGGSGGSlveepknlyktncdlyeklgeygf qnailvlytqkapqvstptiveaarnlgrvgtkcctlpedqrlpcvedylsailnrycllhektpvsehytkccsgslverrp cfsaltvdetyvpkefkaallfhsdictlpekekqikkqtalaelvklikpkataeqlktvmddfaqfldtcckaadkdtcf stegpnlvtrckdalaSGGPGPAGMKGLPGScdlpqtlmlinkraltllvqmrrlsplsclkdrkdfgfpqekv daqqikkagaipvlseltqqilniftskdssaawnifildsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfh rityylrekkhspcawevvraevwralsssanylgrlreekSGGPGPAGMKGLPGSeahkseialllyndlge qhflcglvliafsqylqkcsydehaklvqevtclfaktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepe rnecflqhkddnpslppferpeaeamctsfkenptlfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkes cltpkldgykekalvssvrqGGGGSGGGGSGGSlveepknlyktncdlyeklgeygfqnailviytqkapqvs tptiveaarnlgrvgtkcctlpedqrlpcvedylsailnrycllhektpvsehytkccsgslverrpcfsaltvdetyvpkefk aelltihsdictlpekekqikkqtalaelvklikpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaH HHHHH** 423 ACP202 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSggggsgggSGGPGPAGMKGLPGSggggsgggscdlpqamlinkraltllvqmrrls plsclkdrkclfgfpqekvdaqqikkagaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgv qefpltqedallavrkyfhrityylrelcichspcawevvraevwralsssanylgrlreekggggsgggSGGPGPAG MKGLPGSggggsgggsEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVR QAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDT AVYYCTIGGSLSVSSQGTLVTVSSHHHHHH** 424 ACP203 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgscdlpqtlmlinkraltllvqmrrlsplsclkdrkdfgfpqekvdaq qikkagaipvlseltqqilniftskdssaawnifildsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritv ylrelcichspcawevvraevwralsssanylgrlreeksggpGPAGLYAQpgsEVQLVESGGGLVQP GNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 425 ACP204 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgscdlpqthnlinkraltllvqmrrlsplsclkdrkdfgfpqekvdaqqi klcaqaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhrityyl rekkhspcawevvraevwralsssanylgrlreeksggpALFKSSFPpgsEVQLVESGGGLVQPGNS LRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTI SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 426 ACP205 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpPLAQKLKSSpgscdlpqthnlinkraltllvqmrrlsplsclkdrkdfgfpqekvdaq qikkagaipvlseltqqilniftskdssaawnifildsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritv ylrelcichspcawevvraevwralsssanylgrlreeksggpPLAQKLKSSpgsEVQLVESGGGLVQP GNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 427 ACP206 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgscdlpqthslgsrrtlmllaqmrrislfsclkdrhdfgfpqeefgnqf qkaetipvlhemiqqifnlfstkdssaawdetlldkfytelyqqlndleacviqgvgvtetplmkedsilavrkyfqritlyl kekkyspcawevvraeimrsfslstnlqesliskesggpGPAGLYAQpgsEVQLVESGGGLVQPGN SLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFT ISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 428 ACP207 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgscdlpqthslgsrrtlmllaqmrrislfsclkdrhdfgfpqeefgnqfq kaetipvlhemiqqifnlfstkdssaawdetlldkfytelyqqlndleacviqgvgvtetplmkedsilavrkyfqritlylk ekkyspcawevvraeimrsfslstnlqesliskesggpALFKSSFPpgsEVQLVESGGGLVQPGNSL RLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTIS RDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 429 ACP208 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpPLAQKLKSSpgscdlpqthslgsrrtlmllaqmrrislfsclkdrhdfgfpqeefgnqf qkaetipvlhemiqqifnlfstkdssaawdetlldkfytelyqqlndleacviqgvgvtetplmkedsilavrkyfqritlyl kekkyspcawevvraeimrsfslstnlqesliskesggpPLAQKLKSSpgsEVQLVESGGGLVQPG NSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRF TISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS** 430 ACP211 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdm kilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslr krkrsrcSGGPGPAGMKGLPGScdlpqthnlinkraltllvqmrrlsplsclkdrkclfgfpqekvdaqqikka qaipvlseltqqilniftskdssaawnttlldsfcndlhqqlndlqgclmqqvgvqefpltqedallavrkyfhritvylrek khspcawevvraevwralsssanvlgrlreekSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveek slfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnnpqvqr qafnelirvvhqllpesshkrkrsrcSGGPGPAGMKGLPGSEVQLVESGGGLVQPGNSLRLS CAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISRDN AKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH 431 ACP213 lveepknlvktncdlyeklgeygfqnailviytqkapqvstptiveaarnlgrvgtkcctlpedqrlpcvedylsailnrvcl lhektpvsehytkccsgslverrpcfsaltvdetyvpkefkaelftfhsdictlpekekqikkqtalaelvkhkpkataeqlk tvmdclfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnnyfnssgi dveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskaldcdafmsiakfevnn pqvqrqafnelirvvhqllpesshkrkrsrcSGGPGPAGMKGLPGSlveepknlvktncdlyeklgeygfqn ailvlytqkapqvstptiveaarnlgrvgtkcctlpedqrlpcvedylsailnrycllhektpvsehvtkccsgslverrpcfs altvdetyvpkefkaelft-fhsdictlpekekqikkqtalaelvklikpkataeqlktvmddfaqfldtcckaadkdtcfste gpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdmkil qsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesshkr krsrcSGGPGPAGMKGLPGSlveepknlvktncdlyeklgeygfqnailviytqkapqvstptiveaarnlgr vgtkcctlpedqrlpcvedylsailnrycllhektpvsehvtkccsgslverrpcfsaltvdetyvpkefkaelftfhsdictl pekekqikkqtalaelvklikpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaHHHHHH** 432 ACP214 eahkseialllyndlgeqhflcglvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlr enygeladcctkqepernecflqhkddnpslppferpeaeamctsfkenpttfmghylhevarrhpyfyapellyyaeq yneiltqccaeadkescltpkldgvkekalvssvrqGGGGSGGGGSGGSlveepknlvktncdlyeklgeygf qnailvlytqkapqvstptiveaarnlgrvgtkcctlpedqrlpcvedylsailnrycllhektpvsehytkccsgslverrp cfsaltvdetyvpkefkaetflfhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcf stegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnnyfnssgidveekslfldiwrnwqkdgdm kilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvqrqafnelirvvhqllpesslr krkrsrcSGGPGPAGMKGLPGSeahkseialuyndlgeqhfkglvliafsqylqkcsydehaklvqevtdfa ktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepernecflqhkddnpslppferpeaeamctsfken pttfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkescltpkldgvkekalvssvrqGGGGSGGGG SGGSlveepknlvktncdlyeklgeygfqnailviytqkapqvstptiveaarnlgrvgtkcctlpedqrlpcvedylsa ilnrycllhektpvsehytkccsgslverrpcfsaltvdetyvpkefkaelftfhsdictlpekekqikkqtalaelvkhkpk ataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaSGGPGPAGMKGLPGShgtviesleslnn yfnssgidveekslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsia kfevnnpqvqrqafnelirvvhqllpesslrlukrsrcSGGPGPAGMKGLPGSeahkseiahryndlgeqhflc glvliafsqylqkcsydehaklvqevtdfaktcvadesaancdkslhtlfgdklcaipnlrenygeladcctkqepernec flqhkddnpslppferpeaeamctsfkenptlfmghylhevarrhpyfyapellyyaeqyneiltqccaeadkescltpk ldukekalvssvrqGGGGSGGGGSGGSlveepknlvktncdlyeklgeygfqnailviytqkapqvstptiv eaarnlgrvgtkcctlpedqrlpcvedylsailnrycllhektpvsehytkccsgslverrpcfsaltvdetyvpkefkaelft fhsdictlpekekqikkqtalaelvkhkpkataeqlktvmddfaqfldtcckaadkdtcfstegpnlvtrckdalaHHH HHH** 433 ACP215 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSggggsgggSGGPGPAGMKGLPGSggggsgggshgtviesleslnnyfnssgidvee kslfldiwrnwqkdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlittffsnskakkdafmsiakfevnnpqvq rqafnelirvvhqllpesshkrkrsrcggggsgggSGGPGPAGMKGLPGSggggsgggsEVQLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLY AESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTV SSggggsgggSGGPGPAGMKGLPGSggggsgggshgtviesleslnnyfnssgidveekslfldiwrnwq kdgdmkilqsqiisfylrlfevlkdnqaisnnisvieshlitlffsnskaldcdafmsiakfevnnpqvqrqafneffivvhq llpesshkrkrsrcggggsgggSGGPGPAGMKGLPGSggggsgggsEVQLVESGGGLVQPGN SLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFT ISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHHHH* * 434 ACP240 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSggggsggggsggggsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqssevl gsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistd llfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdi ikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdkisatvicrknasisvraqd iyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidhedi trdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkg mlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstryvtimvmgylssaggggsggggsggggsg gggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNT VKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEAD YYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGR SLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGR FTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHH HHH 435 ACP241 EAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKT CVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQH KDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYA EQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERA FKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAK YMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQE VCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANP PACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQV STPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSE HVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKK QTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVT RCKDALASGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvitcdtpeedgitwadqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltt istdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisv raqthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstryvtinrvmgylssaSGGPGPAG MKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGS RSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGL QAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGG GVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMV TVSSHHHHHH** 436 ACP242 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshs llllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt wstphsyfsltkvqvqgkskrekkdivftdktsatvicrknasisvraqchyyssswsewasvpcsggggsggggsgg ggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretss ttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgead pyrvkmklcillhafstryvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggg gsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLI YYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLF GTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYG MHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMN SLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSSGGPGPAGMKGLPGSEAHKS EIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADE SAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNP SLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNE ILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWA VARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCEN QATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNY AEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYG TVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLV EAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCC SGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAEL VKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDAL AHHHHHH** 437 ACP243 vprdcgckpcictypevssvfifppkpkdvititltpkvtcvvvdiskddpevqfswfvddvevhtaqtqpreeqfnstf rsyselpimhqdwingkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitclffpeditv ewqwngqpaenykntqpimdtdgsyfvyskinvqksnweagniftcsvlheglhnhhtekslshspgkSGGPG PAGMKGLPGSiwellckdvyvveldwypdapgemvvitcdtpeedgitwtldqssevlgsgktltiqvkefgda gqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqg vtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplk nsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvraqthyyssswsewasvp csggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedidheditrdqtstlktclplelh knesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnh ngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsgggg sggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQ QLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQS YDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLS CAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSHHHHHH** 438 ACP244 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqssevlgsgktltiqvkefgdagqytchkggevlshs llllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt wstphsyfsltkvqvqgkskrekkdwftdktsatvicrknasisvraqthyyssswsewasvpcsggggsggggsgg ggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretsst trgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgead pyrvkmklcillhafstrvvtinrvmgylssaSGGPGPAGMKGLPGSggggsggggsggggsggggsggg gsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPGTAPKLLI YYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYTHPALLF GTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYG MHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMN SLRAEDTAVYYCKTHGSHDNWGQGTMVTVSSSGGPGPAGMKGLPGSvprdcgc kpcictypevssvfifppkpkdvltitltpkvtcwvdiskddpevqfswfvddvevhtaqtqpreeqfnstfrsyselpi mhqdwhigkefkcrynsaafpapiektisktkgrpkapqvytipppkeqmakdkvsltcmitdffpeditvewqwn gqpaenykntqpimdtdgsyfvysklnvqksnweagntftcsvlheglhnhhtekslshspgkHHHHHH** 439 ACP245 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtl dqssevlgsgkiltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcw wittistdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyeny tssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltkvqvqgkskrekkdrvftdktsatvicrkna sisvraqthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqunllkttddmvktareklkhyscta edidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnh qqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPA GMKGLPGSggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCS GSRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAIT GLQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLSGGPGPAGMKGLPGSQV QLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYD GSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNW GQGTMVTVSSHHHHHH 440 ACP247 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGMKGLPGSiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtl dqssevlgsgkiltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkifirceaknysgrftcw wittistdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyeny tssffirdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltkvqvqgkskrekkdrvftdktsatvicrkna sisvraqthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhyscta edidheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnh qqiildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssaSGGPGPA GMKGLPGSggggsggggsggggsggggsggggsggggsQVQLQESGGGLVQAGGSLRLSC AASGRTFSSVYDMGWFRQAPGKDREFVARITESARNTRYADSVRGRFTISRDN AKNTVYLQMNNLELEDAAVYYCAADPQTVVVGTPDYWGQGTQVTVSSHHH HHH 636 WW0301 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTSGGPGPAGMKGLPGSEVQLVESGGGLVQ PGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGS GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGL VQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVR GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTV SSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVGW YQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ QYYTYPYTFGGGTKVEIKHHHHHH 637 WW0353 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTSGGPGPAGMKGLPGSVPRDCGCKPCICTV PBVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQ TQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGR PKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNT QPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPG KGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSSGGPGPAGMKGLPGSEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVG TNVGWYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFA TYYCQQYYTYPYTFGGGTKVEIKHHHHHH 638 WW0355 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTSGGPGPAGMKGLPGSGGGGSGGGGSGGG GSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLA WVRQAPGKGLEWVAAIDSSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRA EDTAVYYCARDSNWDALDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCKASQNVGTNVGWYQQKPGKAPKALIYSASFRYSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGGGTKVEIKSGGPG PAGMKGLPGSVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVV DISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSlFRSVSELPIMHQDWLNGK EFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITD FFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNT FTCSVLHEGLHNHHTEKSLSHSPGKHHHHHH 639 WW0365 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTGGGSGGGSGGGSGGGSEVQLVESGGGLV QPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVK GRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGG GSGGGGSGGGGSGGGGSGGGGSGGGGSSGGPGPAGMKGLPGSEVQLVESGG GLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDT VRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTV TVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQNVGTNVG WYQQKPGKAPKALIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQYYTYPYTFGGGTKVEIKHHHHHHEPEA 640 WW0366 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTSGGPGPAGMKGLPGSEVQLVESGGGLVQ PGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHH HHEPEA 641 WW0472 VPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQF SWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAA FPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQ WNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLH NHHTEKSLSHSPGKSGGPGPAGLYAQPGSAPTSSSTKKTQLQLEHLLLDLQMI LNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTL TGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSSGGPGPAGLYAQPGSEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSSGGPGPAGLYAQPGSDIQMTQSPSSLSASVGDRVTITCKAREKLW SAVAWYQQKPGKAPKSLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFA TYYCQQYYTYPYTFGGGTKVEIK 642 WW0473 VPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQF SWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAA FPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQ WNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLH NHHTEKSLSHSPGKSGGPGPAGLYAQPGSAPTSSSTKKTQLQLEHLLLDLQMI LNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTL TGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSSGGPGPAGLYAQPGSEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKAREKLW SAVAWYQQKPGKAPKSLIYSASFRYSGVPSRFSGSGSGTDFTLTISSLQPEDFA TYYCQQYYTYPYTFGGGTKVEIK 643 WW0474 VPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQF SWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAA FPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQ WNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLH NHHTEKSLSHSPGKSGGPGPAGLYAQPGSAPTSSSTKKTQLQLEHLLLDLQMI LNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTL TGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSSGGPGPAGLYAQPGSEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSSGGPGPAGLYAQPGSDIQMTQSPSSLSASVGDRVTITCKVTEKVW GNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQYYTYPYTFGGGTKVEIK 644 WW0475 VPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQF SWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAA FPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQ WNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLH NHHTEKSLSHSPGKSGGPGPAGLYAQPGSAPTSSSTKKTQLQLEHLLLDLQMI LNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTL TGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSSGGPGPAGLYAQPGSEVQLV ESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTY SPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQ GTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKVTEKV WGNVAWYQQKPGKAPISLIYSPSLRKSGVPSRFSGSGSGTDFTLTISSLQPEDF ATYYCQQYYTYPYTFGGGTKVEIK 645 WW0476 VPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQF SWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAA FPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQ WNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLH NHHTEKSLSHSPGKSGGPGPAGLYAQPGSAPTSSSTKKTQLQLEHLLLDLQMI LNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTL TGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSSGGPGPAGLYAQPGSEVQLL ESGGGLVQPGGSLRLSCAASGSIFSANAMGWYRQAPGKGLELVAVISSGGSTN YADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCMYSGSYYYTPNDYW GQGTLVTVSS 646 WW0477 VPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQF SWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAA FPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQ WNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLH NHHTEKSLSHSPGKSGGPGPAGLYAQPGSAPTSSSTKKTQLQLEHLLLDLQMI LNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTL TGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSSGGPGPAGLYAQPGSEVQLL ESGGGLVQPGGSLRLSCAASERIFSTDVMGWYRQAPGKQRELVAVVSARGTT NYLDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYVRETTSPWRIYWG QGTLVTVSS 647 WW0649 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS Monomeric GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS IL-12 SQGTLVTVSSsgGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwildqs (chimeric) sevlgsgktltiqvkefgdagqytchkggevlshsllllhldcedgiwstdilkdqkepluildflrceaknysgrftcwwltt poly- istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf peptide, firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv anti-HSA raqdiyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedi sdAb, scFv dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi Blocker, 2 ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY cleavage AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN sites IGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 454 WW0650 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwildqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhldcedgiwstdilkdqkepluildflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdiyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESG GGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTM VTVSS** 455 WW0651 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwildqss evlgsglaltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdiyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 456 WW0652 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwildqss evlgsglaltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdiyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQ AEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGG VVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYA DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVT VSS** 457 WW0662 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhIckedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisv raqchyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrffilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngethqkppvgeadpyrvkmklcillhafstryvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 458 WW0663 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhIckedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisv raqchyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalcissiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESG GGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYY AeSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMV TVSS** 459 WW0664 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhIckedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisv raqchyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrffilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngethqkppvgeadpyrvkmklcillhafstryvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 460 WW0665 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhIckedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisv raqchyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalcissiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESG GGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYY AeSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMV TVSS** 461 WW0666 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGdNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 462 WW0667 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGdNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESG GGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYY AeSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMV TVSS** 463 WW0668 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 464 WW0669 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESG GGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTM VTVSS** 465 WW0670 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 466 WW0671 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESG GGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYY AeSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMV TVSS** 467 WW0672 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSeSN IGSNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 468 WW0673 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SeSNIGSNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESG GGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTM VTVSS** 469 WW0674 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGeNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 470 WW0675 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGeNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESG GGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYY AeSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMV TVSS** 471 WW0676 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGeeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 472 WW0677 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalcissiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGeeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGL QAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGG GVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMV TVSS** 473 WW0678 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhIckedgiwstdilkdqkepknktflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstryvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 474 WW0679 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhIckedgiwstdilkdqkepknktflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalcissiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESG GGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMV TVSS** 475 WW0680 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstryvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 476 WW0681 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqthyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQ AEDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGG VVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAe SVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTV ss** 477 WW0682 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 635 WW0683 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqthyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGV VQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 478 WW0684 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GdNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 479 WW0685 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdllfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGdNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGV VQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 480 WW0686 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdllfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAED EADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQ PGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 481 WW0687 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdllfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGV VQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYAD SVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTV SS** 482 WW0688 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdllfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAED EADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQ PGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSVK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS** 483 WW0689 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhlckedgiwstdilkdqkepknklflrceaknysgrftcwwltti stdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfslIfcvqvqgkskrekkdryftdktsatvicrknasisvr aqdwyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedllunyqveflamnakllm dpkrqindqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGV VQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 484 WW0690 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhlckedgiwstdilkdqkepknklflrceaknysgrftcwwltti stdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfslIfcvqvqgkskrekkdryftdktsatvicrknasisvr aqdwyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsnillkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefriainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSeSNIG SNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAED EADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQ PGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 485 WW0691 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhlckedgiwstdilkdqkepknklflrceaknysgrftcwwltti stdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsiticvqvqgkskrekkdryftdktsatvicrknasisvr aqdwyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedllunyqveflamnakllm dpkrqindqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSeS NIGSNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGV VQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYAD SVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTV SS** 486 WW0692 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhlckedgiwstdilkdqkepknklflrceaknysgrftcwwltti stdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsiticvqvqgkskrekkdryftdktsatvicrknasisvr aqdwyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsnillkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefriainaalqnhnhqqiil dkgmlvaidelmqslnhngethqkppvgeadpyrvkmklcillhafstryvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GeNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 487 WW0693 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stcliffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqchyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedllunyqveflamnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGeNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGV VQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 488 WW0694 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stcliffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqchyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsmllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiil dkgmlvaidelmqslnhngethqkppvgeadpyrvkmklcillhafstryvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GeeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAED EADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQ PGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 489 WW0695 GSGRDTLYAESVKGRFTIEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS SRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stcliffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqchyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedllunyqveflamnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGeeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGV VQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYAD SVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTV SS** 490 WW0696 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvitcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stcliffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVV QPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS ** 491 WW0697 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGV VQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVS S** 492 WW0698 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdlyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 493 WW0699 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdlyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycli sdfypgavtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 494 WW0700 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkiflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 495 WW0701 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycli sdfypgavtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 496 WW0702 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGdNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 497 WW0703 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfslIfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGdNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycli sdfypgavtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 498 WW0704 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 499 WW0705 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycli sdfypgavtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 500 WW0706 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSeSN IGSNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisclfypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 501 WW0707 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SeSNIGSNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycli sdfypgavtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 502 WW0708 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqdryyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrifilkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGeNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 503 WW0709 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqthyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGeNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycli sdfypgavtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 504 WW0710 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedi dheditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqi ildkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpGPAGLY AQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSN IGeeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycliscifypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 505 WW0711 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpGPAGLYAQpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqs sevlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwltt istdlifsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssf firdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisv raqthyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypc tseeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpGPA GLYAQpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSG SRSNIGeeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGL QAEDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclis dfypgavtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 506 WW0712 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvltcdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdiffsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsitfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqthyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycliscifypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 507 WW0713 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdllfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdfyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGSNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQ AEDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycliscif ypgavtvawkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 508 WW0714 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdllfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdfyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrfdlkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlycliscifypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 509 WW0715 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdllfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdfyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGSeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfyp gavtvawkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 510 WW0716 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdllfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdfyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrfdlkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GdNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 511 WW0717 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdllfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGdNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfyp gavtvawkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 512 WW0718 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAED EADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankativclisdfypga vtvawkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 513 WW0719 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGdeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfyp gavtvawkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 514 WW0720 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSeSNIG SNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAED EADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankativclisdfypga vtvawkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 515 WW0721 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSeS NIGSNdVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfyp gavtvawkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 516 WW0722 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsgALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GeNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAE DEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfypg avtvawkadsspvkagvettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 517 WW0723 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypct seeidheditkdktstveaclpleltknesclnsretsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllm dpkrqifldqnmlavidelmqalnfnsetvpqkssleepdfyktkiklcillhafriravtidrvmsylnassggpALFK SSFPpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRS NIGeNTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQA EDEADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfyp gavtvawkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 518 WW0724 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss evlgsgktltiqvkefgdagqytchkggevlshsllllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwltti stdltfsvkssrgssdpqgvtcgaatlsaervrgdnkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssff irdiikpdppknlqlkplknsrqvevsweypdtwstphsyfsltfcvqvqgkskrekkdrvftdktsatvicrknasisvr aqdlyyssswsewasvpcsggggsggggsggggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedid heditrdqtstlktclplelhknesclatretssttrgsclppqktslmmticlgsiyedlkmyqtefciainaalqnhnhqqiil dkgmlvaidelmqslnhngetlrqkppvgeadpyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSF PpgsggggsggggsggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNI GeeTVKWYQQLPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAED EADYYCQSYDRYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankativclisdfypga vtvawkadsspvkagvetttpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 519 WW0725 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSsggpALFKSSFPpgsiwelkkdvyvveldwypdapgemvvlicdtpeedgitwtldqss 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ssleepdfyktkiklcillhafriravtidrvmsylnassggpGPAGLYAQpgsEVQLVESGGGLVQPG NSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRF TISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsgggg sggggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGdeTVKWYQQ LPGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSY DRYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSC AASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS** 527 WW0769 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwildqssevlgsgktltiqvkefgdagqytchkggevlshs llllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt wstphsyfshfcvqvqgkskrekkchvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsgg ggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgs clppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgead 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RYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSVKGRFTISRDNSK NTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS** 533 WW0798 iwelkkdvyvveldwypdapgemvvItcdtpeedgitwtldqssevIgsgktItiqvkefgdagqytchkggevIshs llllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwIttistdIffsvkssrgssdpqgvtcgaatIsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhlayenytssffirdiikpdppknIqlkplknsrqvevsweypdt wstphsyfshfcvqvqgkskrekkdwftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsgg ggsrvipvsgparcIsqsrnlIkttddmvktareklkhysctaedidheditrdqtstIktclplelhknesclatretssttrgs cIppqktsImmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetIrqkppvgead pyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSFPpgsEVQLVESGGGLVQPGNSLR LSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISR DNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsgggg sggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGdeTVKWYQQLPGT APKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYT HPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCAASGF TFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS** 534 WW0799 iwelkkdvyvveldwypdapgemvvItcdtpeedgitwildqssevIgsgktItiqvkefgdagqytchkggevIshs llllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwIttistdIffsvkssrgssdpqgvtcgaatIsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhlayenytssffirdiikpdppknIqlkplknsrqvevsweypdt wstphsyfshfcvqvqgkskrekkdwftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsgg ggsrnIpvatpdpgmfpclhhsqnlIraysnmlqkarqtlefypctseeidheditkdktstveacIpleltknescInsre tsfitngsclasrktsfmmalcIssiyedlkmyqvefktmnakIlmdpkrqifldqnmlavidelmqaInfnsetvpqk ssleepdfyktkiklcillhafriravtidrvmsylnassggpALFKSSFPpgsEVQLVESGGGLVQPGN SLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFT ISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsg gggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGdeTVKWYQQL PGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYD RYTHPALLFGTGTKVTVLggggsggggsggggsQVQLVESGGGVVQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKGLEWVAFIRYeGSNKYYAeSVKGRFTISRDNSK NTLYLQMNSLRAEDTAVYYCKTHGSHDNWGQGTMVTVSS** 535 WW0800 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwildqssevlgsgktltiqvkefgdagqytchkggevlshs llllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt wstphsyfshfcvqvqgkskrekkdwftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsgg ggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgs clppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgead pyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSFPpgsEVQLVESGGGLVQPGNSLR LSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISR DNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsgggg sggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQLPG TAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRY THPALLFGTGIKVTVLgqpkaapsvtlfppsseelqankatlycliscifypgavtvawkadsspvkagvett tpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 536 WW0801 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwildqssevlgsgktltiqvkefgdagqytchkggevlshs llllhkkedgiwstdilkdqkepknkifirceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt wstphsyfshfcvqvqgkskrekkdwftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsgg ggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypctseeidheditkdktstveaclpleltknesclnsre tsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllmdpkrqifldqnmlavidelmqalnfnsetvpqk ssleepdfyktkiklcillhafriravtidrvmsylnassggpALFKSSFPpgsEVQLVESGGGLVQPGN SLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFT ISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsg gggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGSNTVKWYQQL PGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYD RYTHPALLFGTGIKVTVLgqpkaapsvtlfppsseelqankatlyclisdfypgavtvawkadsspvkag vettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 537 WW0802 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwildqssevlgsgktltiqvkefgdagqytchkggevlshs llllhkkedgiwstdilkdqkepknktflrceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt wstphsyfshfcvqvqgkskrekkchvftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsgg ggsrvipvsgparclsqsrnllkttddmvktareklkhysctaedidheditrdqtstlktclplelhknesclatretssttrgs clppqktslmmticlgsiyedlkmyqtefqainaalqnhnhqqiildkgmlvaidelmqslnhngetlrqkppvgead pyrvkmklcillhafstrvvtinrvmgylssasggpALFKSSFPpgsEVQLVESGGGLVQPGNSLR LSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFTISR DNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsgggg sggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGdeTVKWYQQLPGT APKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRYT HPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankativclisdfypgavtvawkadsspvkagvettt pskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 538 WW0803 iwelkkdvyvveldwypdapgemvvitcdtpeedgitwfldqssevlgsgktltiqvkefgdagqytchkggevlshs llllhkkedgiwstdilkdqkepknkffirceaknysgrftcwwlttistdltfsvkssrgssdpqgvtcgaatlsaervrgd nkeyeysvecqedsacpaaeeslpievmvdavhklkyenytssffirdiikpdppknlqlkplknsrqvevsweypdt wstphsyfshfcvqvqgkskrekkdwftdktsatvicrknasisvraqdryyssswsewasvpcsggggsggggsgg ggsrnlpvatpdpgmfpclhhsqnllraysnmlqkarqtlefypctseeidheditkdktstveaclpleltknesclnsre tsfitngsclasrktsfmmalclssiyedlkmyqvefktmnakllmdpkrqifldqnmlavidelmqalnfnsetvpqk ssleepdfyktkiklcillhafriravtidrvmsylnassggpALFKSSFPpgsEVQLVESGGGLVQPGN SLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKGRFT ISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSggggsggggsg gggsggggsggggsggggsQSVLTQPPSVSGAPGQRVTISCSGSRSNIGdeTVKWYQQL PGTAPKLLIYYNDQRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYD RYTHPALLFGTGTKVTVLgqpkaapsvtlfppsseelqankatlyclisdfypgavtvawkadsspvkag vettlpskqsnnkyaassylsltpeqwkshrsyscqvthegstvektvaptecs** 539 WW0643 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSCDLPHTYNLRNKRALKVLAQMRRLTPL SCLKDRKDFGFPLEKVDAQQIQKAQSIPVLRDLTQQILNLFASKDSSAAWNAT LLDSFCNDLHQQLNDLQGCLMQQVGVQESPLTQEDSLLAVRIYFHRITVFLRE KKHSPCAWEVVRAEVWRALSSSANVLGRLREEKASGGPGPAGLYAQPGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGS GRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQ GTLVTVSS 540 WW0644 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSCDLPHTYNLRNKRALKVLAQMRRLTPLS CLKDRKDFGFPLEKVDAQQIQKAQSIPVLRDLTQQILNLFASKDSSAAWNATL LDSFCNDLHQQLNDLQGCLMQQVGVQESPLTQEDSLLAVRIYFHRITVFLREK KHSPCAWEVVRAEVWRALSSSANVLGRLREEKASGGPALFKSSFPPGSEVQL VESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGR DTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSS 541 WW0645 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSCNLSQTHSLNNRRTLMLMAQMRRISPFS CLKDRHDFEFPQEEFDGNQFQKAQAISVLHEMMQQTFNLFSTKNSSAAWDET LLEKFYIELFQQMNDLEACVIQEVGVEETPLMNEDSILAVKKYFQRITLYLME KKYSPCAWEVVRAEIMRSLSFSTNLQKRLRRKDSGGPGPAGLYAQPGSEVQL VESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGR DTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSS 542 WW0646 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSCNLSQTHSLNNRRTLMLMAQMRRISPFSC LKDRHDFEFPQEEFDGNQFQKAQAISVLHEMMQQTFNLFSTKNSSAAWDETL LEKFYIELFQQMNDLEACVIQEVGVEETPLMNEDSILAVKKYFQRITLYLMEK KYSPCAWEVVRAEIMRSLSFSTNLQKRLRRKDSGGPALFKSSFPPGSEVQLVES GGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSS 543 WW0647 CDLPHTYNLRNKRALKVLAQMRRLTPLSCLKDRKDFGFPLEKVDAQQIQKAQ SIPVLRDLTQQILNLFASKDSSAAWNATLLDSFCNDLHQQLNDLQGCLMQQV GVQESPLTQEDSLLAVRIYFHRITVFLREKKHSPCAWEVVRAEVWRALSSSAN VLGRLREEKAHHHHHH 544 WW0648 CNLSQTHSLNNRRTLMLMAQMRRISPFSCLKDRHDFEFPQEEFDGNQFQKAQ AISVLHEMMQQTFNLFSTKNSSAAWDETLLEKFYIELFQQMNDLEACVIQEVG VEETPLMNEDSILAVKKYFQRITLYLMEKKYSPCAWEVVRAEIMRSLSFSTNL QKRLRRKDHHHHHH 545 WW0781 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSCDLPQTHSLGSRRTLMLLAQMRRISLFS CLKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLD KFYTELYQQLNDLEACVIQGVGVEETPLMKEDSILAVRKYFQRITLYLKEKKY SPCAWEVVRAEIMRSFSLSTNLQESLRSKESGGPGPAGLYAQPGSEVQLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLY AESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTV SS 546 WW0782 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSCNLSQTHSLNNRRTLMLMAQMRRISPFS CLKDRHDFEFPQEEFDGNQFQKAQAISVLHEMMQQTFNLFSTKDSSAAWDET LLEKFYIELFQQMNDLEACVIQEVGVEETPLMNEDSILAVKKYFQRITLYLME KKYSPCAWEVVRAEIMRSLSFSTNLQKRLRRKDSGGPGPAGLYAQPGSEVQL VESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGR DTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSS 547 WW0783 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSCDLPQTHSLNNRRTLMLMAQMRRISPFS CLKDRHDFEFPQEEFDGNQFQKAQAISVLHEMMQQTFNLFSTKDSSAAWDET LLEKFYIELFQQMNDLEACVIQEVGVEETPLMNEDSILAVKKYFQRITLYLME KKYSPCAWEVVRAEIMRSLSFSTNLQKRLRRKDSGGPGPAGLYAQPGSEVQL VESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGR DTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGT LVTVSS 548 WW0784 CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIP VLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVEE TPLMKEDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESL RSKEHHHHHH 549 WW0785 CNLSQTHSLNNRRTLMLMAQMRRISPFSCLKDRHDFEFPQEEFDGNQFQKAQ AISVLHEMMQQTFNLFSTKDSSAAWDETLLEKFYIELFQQMNDLEACVIQEVG VEETPLMNEDSILAVKKYFQRITLYLMEKKYSPCAWEVVRAEIMRSLSFSTNL QKRLRRKDHHHHHH 550 WW0786 CDLPQTHSLNNRRTLMLMAQMRRISPFSCLKDRHDFEFPQEEFDGNQFQKAQ AISVLHEMMQQTFNLFSTKDSSAAWDETLLEKFYIELFQQMNDLEACVIQEVG VEETPLMNEDSILAVKKYFQRITLYLMEKKYSPCAWEVVRAEIMRSLSFSTNL QKRLRRKDHHHHHH 551 WW0815 EAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKT CVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQH KDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYA EQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERA FKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAK YMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQE VCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANP PACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQV STPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSE HVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKK QTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVT RCKDALASGGPALFKSSFPPGSCDLPQTHNLRNKRALTLLVQMRRLSPLSCLK DRKDFGFPQEKVDAQQIKKAQAIPVLSELTQQILNIFTSKDSSAAWNTTLLDSF CNDLHQQLNDLQGCLMQQVGVQEFPLTQEDALLAVRKYFHRITVYLREKKH SPCAWEVVRAEVWRALSSSANVLGRLREEKSGGPALFKSSFPPGSEAHKSEIA HRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAA NCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLP PFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILT QCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVA RLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQA TISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEA KDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVL AEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAA RNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGS LVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVK HKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAH HHHHH 552 WW0816 EAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKT CVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQH KDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYA EQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERA FKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAK YMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQE VCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANP PACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQV STPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSE HVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKK QTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVT RCKDALASGGPALFKSSFPPGSCDLPHTYNLRNKRALKVLAQMRRLTPLSCLK DRKDFGFPLEKVDAQQIQKAQSIPVLRDLTQQILNLFASKDSSAAWNATLLDS FCNDLHQQLNDLQGCLMQQVGVQESPLTQEDSLLAVRIYFHRITVFLREKKHS PCAWEVVRAEVWRALSSSANVLGRLREEKASGGPALFKSSFPPGSEAHKSEIA HRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESAA NCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSLP PFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEILT QCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAVA RLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQA TISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAEA KDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTVL AEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEAA RNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSGS LVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELVK HKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALAH HHHHH 553 WW0817 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSCDLPQTHNLRNKRALTLLVQMRRLSPLSC LKDRKDFGFPQEKVDAQQlKKAQAIPVLSELTQQILNIFTSKDSSAAWNTTLLD SFCNDLHQQLNDLQGCLMQQVGVQEFPLTQEDALLAVRKYFHRITVYLREKK HSPCAWEVVRAEVWRALSSSANVLGRLREEKSGGPALFKSSFPPGSEAHKSEI AHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVADESA ANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDDNPSL PPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQYNEIL TQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKAWAV ARLSQlFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYMCENQ ATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCKNYAE AKDVFLGIFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPACYGTV LAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPTLVEA ARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTKCCSG SLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTALAELV KHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCKDALA HHHHHH 554 WW0818 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSCDLPHTYNLRNKRALKVLAQMRRLTPLS CLKDRKDFGFPLEKVDAQQIQKAQSIPVLRDLTQQILNLFASKDSSAAWNATL LDSFCNDLHQQLNDLQGCLMQQVGVQESPLTQEDSLLAVRIYFHRITVFLREK KHSPCAWEVVRAEVWRALSSSANVLGRLREEKASGGPALFKSSFPPGSEAHK SEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKTCVAD ESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQHKDD NPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYAEQY NEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERAFKA WAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAKYM CENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQEVCK NYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANPPAC YGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQVSTPT LVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSEHVTK CCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKKQTAL AELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVTRCK DALAHHHHHH 555 WW0819 EAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKT CVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQH KDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYA EQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERA FKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAK YMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQE VCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANP PACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQV STPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSE HVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKK QTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVT RCKDALASGGPALFKSSFPPGSCDLPQTHNLRNKRALTLLVQMRRLSPLSCLK DRKDFGFPQEKVDAQQIKKAQAIPVLSELTQQILNIFTSKDSSAAWNTTLLDSF CNDLHQQLNDLQGCLMQQVGVQEFPLTQEDALLAVRKYFHRITVYLREKKH SPCAWEVVRAEVWRALSSSANVLGRLREEKSGGPALFKSSFPPGSEVQLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLY AESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTV SSHHHHHH 556 WW0820 EAHKSEIAHRYNDLGEQHFKGLVLIAFSQYLQKCSYDEHAKLVQEVTDFAKT CVADESAANCDKSLHTLFGDKLCAIPNLRENYGELADCCTKQEPERNECFLQH KDDNPSLPPFERPEAEAMCTSFKENPTTFMGHYLHEVARRHPYFYAPELLYYA EQYNEILTQCCAEADKESCLTPKLDGVKEKALVSSVRQRMKCSSMQKFGERA FKAWAVARLSQTFPNADFAEITKLATDLTKVNKECCHGDLLECADDRAELAK YMCENQATISSKLQTCCDKPLLKKAHCLSEVEHDTMPADLPAIAADFVEDQE VCKNYAEAKDVFLGTFLYEYSRRHPDYSVSLLLRLAKKYEATLEKCCAEANP PACYGTVLAEFQPLVEEPKNLVKTNCDLYEKLGEYGFQNAILVRYTQKAPQV STPTLVEAARNLGRVGTKCCTLPEDQRLPCVEDYLSAILNRVCLLHEKTPVSE HVTKCCSGSLVERRPCFSALTVDETYVPKEFKAETFTFHSDICTLPEKEKQIKK QTALAELVKHKPKATAEQLKTVMDDFAQFLDTCCKAADKDTCFSTEGPNLVT RCKDALASGGPALFKSSFPPGSCDLPHTYNLRNKRALKVLAQMRRLTPLSCLK DRKDFGFPLEKVDAQQIQKAQSIPVLRDLTQQILNLFASKDSSAAWNATLLDS FCNDLHQQLNDLQGCLMQQVGVQESPLTQEDSLLAVRIYFHRITVFLREKKHS PCAWEVVRAEVWRALSSSANVLGRLREEKASGGPALFKSSFPPGSEVQLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLY AESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTV SSHHHHHH 557 WW0821 DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKT CVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQ HKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFF AKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGER AFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADL AKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKD VCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAAD PHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQV STPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVS DRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIK KQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKL VAASQAALGLSGGPALFKSSFPPGSCDLPQTHSLGSRRTLMLLAQMRRISLFSC LKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDK FYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYS PCAWEVVRAEIMRSFSLSTNLQESLRSKESGGPALFKSSFPPGSDAHKSEVAHR FKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENC DKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPR LVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTE CCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVAR LSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSI SSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKD VFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDE FKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRN LGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESL VNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKH KPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL 558 WW0822 DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKT CVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQ HKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFF AKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGER AFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADL AKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKD VCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAAD PHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQV STPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVS DRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIK KQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKL VAASQAALGLSGGPALFKSSFPPGSCNLSQTHSLNNRRTLMLMAQMRRISPFS CLKDRHDFEFPQEEFDGNQFQKAQAISVLHEMMQQTFNLFSTKNSSAAWDET LLEKFYIELFQQMNDLEACVIQEVGVEETPLMNEDSILAVKKYFQRITLYLME KKYSPCAWEVVRAEIMRSLSFSTNLQKRLRRKDSGGPALFKSSFPPGSDAHKS EVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADE SAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDN PNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYK AAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKA WAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYIC ENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKN YAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECY AKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTL VEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVT KCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTA LVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAAS QAALGL 559 WW08 31 DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKT CVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQ HKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFF AKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGER AFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADL AKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKD VCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAAD PHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQV STPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVS DRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIK KQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKL VAASQAALGLSGGPALFKSSFPPGSCDLPQTHSLGNRRALILLAQMRRISPFSC LKDRHDFEFPQEEFDDKQFQKAQAISVLHEMIQQTFNLFSTKDSSAALDETLL DEFYIELDQQLNDLESCVMQEVGVIESPLMYEDSILAVRKYFQRITLYLTEKKY SSCAWEVVRAEIMRSFSLSINLQKRLKSKESGGPALFKSSFPPGSDAHKSEVAH RFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAEN CDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLP RLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFT ECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVA RLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQD SISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEA KDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVF DEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVS RNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTE SLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELV KHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALG L 560 WW0832 DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKT CVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQ HKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFF AKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGER AFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADL AKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKD VCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAAD PHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQV STPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVS DRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIK KQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKL VAASQAALGLSGGPALFKSSFPPGSCDLPQTHSLGNRRALILLAQMGRISHFSC LKDRYDFGFPQEVFDGNQFQKAQAISAFHEMIQQTFNLFSTKDSSAAWDETLL DKFYIELFQQLNDLEACVTQEVGVEEIALMNEDSILAVRKYFQRITLYLMGKK YSPCAWEVVRAEIMRSFSFSTNLQKGLRRKDSGGPALFKSSFPPGSDAHKSEV AHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESA ENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPN LPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAA FTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWA VARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICEN QDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAK VFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVE VSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKC CTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALV ELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQA ALGL 561 WW0833 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSCDLPQTHSLGNRRALILLAQMRRISPFSCL KDRHDFEFPQEEFDDKQFQKAQAISVLHEMIQQTFNLFSTKDSSAALDETLLD EFYIELDQQLNDLESCVMQEVGVIESPLMYEDSILAVRKYFQRITLYLTEKKYS SCAWEVVRAEIMRSFSLSINLQKRLKSKESGGPALFKSSFPPGSEVQLVESGGG LVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAES VKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS 562 WW0834 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSCDLPQTHSLGNRRALILLAQMGRISHFSCL KDRYDFGFPQEVFDGNQFQKAQAISAFHEMIQQTFNLFSTKDSSAAWDETLLD KFYIELFQQLNDLEACVTQEVGVEEIALMNEDSILAVRKYFQRITLYLMGKKY SPCAWEVVRAEIMRSFSFSTNLQKGLRRKDSGGPALFKSSFPPGSEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS 563 WW0737 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSINYKQLQLQERTNIRKCQELLEQLNGKIN LTYRADFKIPMEMTEKMQKSYTAFAIQEMLQNVFLVFRNNFSSTGWNETIVV RLLDELHQQTVFLKTVLEEKQEERLTWEMSSTALHLKSYYWRVQRYLKLMK YNSYAWMVVRAEIFRNFLIIRRLTRNFQNSGGPGPAGLYAQPGSEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS 564 WW0738 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSINYKQLQLQERTNIRKCQELLEQLNGKINL TYRADFKIPMEMTEKMQKSYTAFAIQEMLQNVFLVFRNNFSSTGWNETIVVR LLDELHQQTVFLKTVLEEKQEERLTWEMSSTALHLKSYYWRVQRYLKLMKY NSYAWMVVRAEIFRNFLIIRRLTRNFQNSGGPALFKSSFPPGSEVQLVESGGGL VQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESV KGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS 565 WW0739 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSINYKQLQLQERTNIRKSQELLEQLNGKIN LTYRADFKIPMEMTEKMQKSYTAFAIQEMLQNVFLVFRNNFSSTGWNETIVV RLLDELHQQTVFLKTVLEEKQEERLTWEMSSTALHLKSYYWRVQRYLKLMK YNSYAWMVVRAEIFRNFLIIRRLTRNFQNSGGPGPAGLYAQPGSEVQLVESGG GLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYA ESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS 566 WW0740 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSINYKQLQLQERTNIRKSQELLEQLNGKINL TYRADFKIPMEMTEKMQKSYTAFAIQEMLQNVFLVFRNNFSSTGWNETIVVR LLDELHQQTVFLKTVLEEKQEERLTWEMSSTALHLKSYYWRVQRYLKLMKY NSYAWMVVRAEIFRNFLIIRRLTRNFQNSGGPALFKSSFPPGSEVQLVESGGGL VQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESV KGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS 567 WW0741 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSMSYNLLGFLQRSSNFQCQKLLWQLNGR LEYCLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWNE TIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLK AKEYSHCAWTIVRVEILRNFYFINRLTGYLRNSGGPGPAGLYAQPGSEVQLVE SGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSS 568 WW0742 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSMSYNLLGFLQRSSNFQCQKLLWQLNGRL EYCLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWNET IVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLKA KEYSHCAWTIVRVEILRNFYFINRLTGYLRNSGGPALFKSSFPPGSEVQLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLY AESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTV SS 569 WW0743 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSMSYNLLGFLQRSSNFQSQKLLWQLNGR LEYCLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWNE TIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLK AKEYSHCAWTIVRVEILRNFYFINRLTGYLRNSGGPGPAGLYAQPGSEVQLVE SGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSS 570 WW0744 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPALFKSSFPPGSMSYNLLGFLQRSSNFQSQKLLWQLNGRL EYCLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWNET IVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLKA KEYSHCAWTIVRVEILRNFYFINRLTGYLRNSGGPALFKSSFPPGSEVQLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLY AESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTV SS 571 WW0745 INYKQLQLQERTNIRKCQELLEQLNGKINLTYRADFKIPMEMTEKMQKSYTAF AIQEMLQNVFLVFRNNFSSTGWNETIVVRLLDELHQQTVFLKTVLEEKQEERL TWEMSSTALHLKSYYWRVQRYLKLMKYNSYAWMVVRAEIFRNFLIIRRLTR NFQNHHHHHH 572 WW0746 INYKQLQLQERTNIRKSQELLEQLNGKINLTYRADFKIPMEMTEKMQKSYTAF AIQEMLQNVFLVFRNNFSSTGWNETIVVRLLDELHQQTVFLKTVLEEKQEERL TWEMSSTALHLKSYYWRVQRYLKLMKYNSYAWMVVRAEIFRNFLIIRRLTR NFQNHHHHHH 573 WW0747 MSYNLLGFLQRSSNFQCQKLLWQLNGRLEYCLKDRMNFDIPEEIKQLQQFQK EDAALTIYEMLQNIFAIFRQDSSSTGWNETIVENLLANVYHQINHLKTVLEEKL EKEDFTRGKLMSSLHLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNFYFINR LTGYLRNHHHHHH 574 WW0748 MSYNLLGFLQRSSNFQSQKLLWQLNGRLEYCLKDRMNFDIPEEIKQLQQFQKE DAALTIYEMLQNIFAIFRQDSSSTGWNETIVENLLANVYHQINHLKTVLEEKLE KEDFTRGKLMSSLHLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNFYFINRL TGYLRNHHHHHH 575 WW0787 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSMSYNLLGFLQRSSNFQCQKLLWQLNGR LEYCLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWQE TIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLK AKEYSHCAWTIVRVEILRNFYFINRLTGYLRNSGGPGPAGLYAQPGSEVQLVE SGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSS 576 WW0788 EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSIS GSGRDTLYAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVS SQGTLVTVSSSGGPGPAGLYAQPGSMSYNLLGFLQRSSNFQSQKLLWQLNGR LEYCLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWQE TIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLK AKEYSHCAWTIVRVEILRNFYFINRLTGYLRNSGGPGPAGLYAQPGSEVQLVE SGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTL YAESVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVT VSS 577 WW0789 MSYNLLGFLQRSSNFQCQKLLWQLNGRLEYCLKDRMNFDIPEEIKQLQQFQK EDAALTIYEMLQNIFAIFRQDSSSTGWQETIVENLLANVYHQINHLKTVLEEKL EKEDFTRGKLMSSLHLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNFYFINR LTGYLRNHHHHHH 578 WW0790 MSYNLLGFLQRSSNFQSQKLLWQLNGRLEYCLKDRMNFDIPEEIKQLQQFQKE DAALTIYEMLQNIFAIFRQDSSSTGWQETIVENLLANVYHQINHLKTVLEEKLE KEDFTRGKLMSSLHLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNFYFINRL TGYLRNHHHHHH 579 WW0729 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTSGGPGGGGSGGGPGSEVQLVESGGGLVQ PGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGS GGGGSGGGGSGGGGSGGGGSGGGGSSGGPGGGGSGGGPGSEVQLVESGGGL VQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVR GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC 580 WW0734 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTSGGPGPAGMKGLPGSEVQLVESGGGLVQ PGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGS GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGL VQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVR GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC 581 WW0735 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTSGGPGPAGLYAQPGSEVQLVESGGGLVQP GNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGS GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGL VQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVR GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC 582 WW0736 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTSGGPALFKSSFPPGSEVQLVESGGGLVQP GNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGS GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGL VQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAIDSSSYTYSPDTVR GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDALDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC 583 WW0792 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTLAWVRQAPGKGLEWVAAID SSSYTYSPDTVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDSNWDAL DYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKRVEPKSCHHHHHH 584 WW0061 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATEL KHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLTSGGPGPAGMKGLPGSEVQLVESGGGLVQ PGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYAESVKG RFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSHHHH HH 585 ACP293 QVQLQESGGGLVQTGGSLRLSCTTSGTIFSGYTMGWYRQAPGEQRELVAVISG (WW0237) GGDTNYADSVKGRFTISRDNTKDTMYLQMNSLKPEDTAVYYCYSREVTPPW KLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 586 ACP294 QVQLQESGGGLVQEGGSLRLSCAASERIFSTDVMGWYRQAAEKQRELVAVVS (WW0238) ARGTTNYLDAVKGRFTISRDNARNTLTLQMNDLKPEDTASYYCYVRETTSPW RIYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 587 ACP295 QVQLQESGGGLVQAGGSLRLSCAASGSlFSANAMGWYRQAPGKQRELVAVIS (WW0239) SGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCMYSGSYYY TPNDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH 588 ACP315 EVQLLESGGGLVQPGGSLRLSCAASGSIFSANAMGWYRQAPGKQRELVAVISS (WW0368) GGSTNYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCMYSGSYYYTP NDYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 589 ACP316 EVQLLESGGGLVQPGGSLRLSCAASGSIFSANAMGWYRQAPGKGLELVAVISS (WW0369) GGSTNYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCMYSGSYYYTP NDYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 590 ACP317 EVQLLESGGGLVQPGGSLRLSCAASGSIFSANAMGWVRQAPGKGLEWVSVIS (WW0370) SGGSTNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCMYSGSYYYT PNDYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 591 ACP318 QVQLLESGGGLVQPGGSLRLSCAASGSIFSANAMGWYRQAPGKQRELVAVIS (WW0371) SGGSTNYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCMYSGSYYYT PNDYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 592 ACP319 EVQLLESGGGLVQPGGSLRLSCAASGSIFSANAMGWYRQAPGKGRELVAVISS (WW0372) GGSTNYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCMYSGSYYYTP NDYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 593 ACP320 QVQLLESGGGLVQAGGSLRLSCAASGSIFSANAMGWYRQAPGKQRELVAVIS (WW0373) SGGSTNYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCMYSGSYYYT PNDYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 594 ACP321 EVQLLESGGGLVQPGGSLRLSCAASERIFSTDVMGWYRQAPGKQRELVAVVS (WW0374) ARGTTNYLDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYVRETTSPW RIYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 595 ACP322 EVQLLESGGGLVQPGGSLRLSCAASERIFSTDVMGWYRQAPGKGLELVAVVS (WW0375) ARGTTNYLDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYVRETTSPW RIYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 596 ACP323 EVQLLESGGGLVQPGGSLRLSCAASERIFSTDVMGWVRQAPGKGLEWVSVVS (WW0376) ARGTTNYLDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYVRETTSPW RIYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 597 ACP324 QVQLLESGGGLVQPGGSLRLSCAASERIFSTDVMGWYRQAPGKQRELVAVVS (WW0377) ARGTTNYLDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYVRETTSPW RIYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 598 ACP325 EVQLLESGGGLVQPGGSLRLSCAASERIFSTDVMGWYRQAPGKGRELVAVVS (WW0378) ARGTTNYLDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYVRETTSPW RIYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 599 ACP326 QVQLLESGGGLVQEGGSLRLSCAASERIFSTDVMGWYRQAAGKQRELVAVVS (WW0379) ARGTTNYLDAVKGRFTISRDNSKNTLYLQMNSLRAEDTASYYCYVRETTSPW RIYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 600 ACP327 EVQLLESGGGLVQPGGSLRLSCAASERIFSTDVMGWYRQAPGKGLELVAVVS (WW0380) ARGTTNYLDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYVRETTSPW RIYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 601 ACP328 EVQLLESGGGLVQPGGSLRLSCATSGTIFSGYTMGWYRQAPGKQRELVAVISG (WW0381) GGDTNYADSVKGRFTISRDNSKDTMYLQMNSLRAEDTAVYYCYSREVTPPW KLYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 602 ACP329 EVQLLESGGGLVQPGGSLRLSCATSGTIFSGYTMGWYRQAPGKGLELVAVISG (WW0382) GGDTNYADSVKGRFTISRDNSKDTMYLQMNSLRAEDTAVYYCYSREVTPPW KLYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 603 ACP330 EVQLLESGGGLVQPGGSLRLSCAASGTIFSGYTMGWVRQAPGKGLEWVSVIS (WW0383) GGGDTNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCYSREVTPPW KLYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 604 ACP331 QVQLLESGGGLVQPGGSLRLSCATSGTIFSGYTMGWYRQAPGKQRELVAVIS (WW0384) GGGDTNYADSVKGRFTISRDNSKDTMYLQMNSLRAEDTAVYYCYSREVTPP WKLYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 605 ACP332 EVQLLESGGGLVQPGGSLRLSCATSGTIFSGYTMGWYRQAPGKQRELVAVISG (WW0385) GGDTNYADSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCYSREVTPPW KLYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 606 ACP333 EVQLLESGGGLVQPGGSLRLSCATSGTIFSGYTMGWYRQAPGKGRELVAVISG (WW0386) GGDTNYADSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCYSREVTPPW KLYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 607 ACP334 QVQLLESGGGLVQTGGSLRLSCATSGTIFSGYTMGWYRQAPGKQRELVAVIS (WW0387) GGGDTNYADSVKGRFTISRDNSKDTMYLQMNSLRAEDTAVYYCYSREVTPP WKLYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 608 ACP335 EVQLLESGGGLVQPGGSLRLSCATSGTIFSGYTMGWYRQAPGKGLELVAVISG (WW0388_ GGDTNYADSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCYSREVTPPW KLYWGQGTLVTVSSAAAYPYDVPDYGSHHHHHH 609 MMP14_1 GPAGLYAQ 610 MMP9_1 GPAGMKGL 611 FAPa_1 PGGPAGIG 612 CTSL1_1 ALFKSSFP 613 CTSL1_2 ALFFSSPP 614 ADAM17_1 LAQRLRSS 615 ADAM17_2 LAQKLKSS 616 ALU30-1 GALFKSSFPSGGGPAGLYAQGGSGKGGSGK 617 ALU30-2 RGSGGGPAGLYAQGSGGGPAGLYAQGGSGK 618 ALU30-3 KGGGPAGLYAQGPAGLYAQGPAGLYAQGSR 619 ALU30-4 RGGPAGLYAQGGPAGLYAQGGGPAGLYAQK 620 ALU30-5 KGGALFKSSFPGGPAGIGPLAQKLKSSGGS 621 ALU30-6 SGGPGGPAGIGALFKSSFPLAQKLKSSGGG 622 ALU30-7 RGPLAQKLKSSALFKSSFPGGPAGIGGGGK 623 ALU30-8 GGGALFKSSFPLAQKLKSSPGGPAGIGGGR 624 ALU30-9 RGPGGPAGIGPLAQKLKSSALFKSSFPGGG 625 ALU30-10 RGGPLAQKLKSSPGGPAGIGALFKSSFPGK 626 ALU30-11 RSGGPAGLYAQALFKSSFPLAQKLKSSGGG 627 ALU30-12 GGPLAQKLKSSALFKSSFPGPAGLYAQGGR 628 ALU30-13 GGALFKSSFPGPAGLYAQPLAQKLKSSGGK 629 ALU30-14 RGGALFKSSFPLAQKLKSSGPAGLYAQGGK 630 ALU30-15 RGGGPAGLYAQPLAQKLKSSALFKSSFPGG 631 ALU30-16 SGPLAQKLKSSGPAGLYAQALFKSSFPGSK 632 ALU30-17 KGGPGGPAGIGPLAQRLRSSALFKSSFPGR 633 ALU30-18 KSGPGGPAGIGALFFSSPPLAQKLKSSGGR 634 ALU30-19 SGGFPRSGGSFNPRTFGSKRKRRGSRGGGG

INCORPORATION BY REFERENCE

The entire disclosures of all patent and non-patent publications cited herein are each incorporated by reference in their entireties for all purposes.

OTHER EMBODIMENTS

The disclosure set forth above may encompass multiple distinct inventions with independent utility. Although each of these inventions has been disclosed in its preferred form(s), the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense, because numerous variations are possible. The subject matter of the inventions includes all novel and nonobvious combinations and subcombinations of the various elements, features, functions, and/or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Inventions embodied in other combinations and subcombinations of features, functions, elements, and/or properties may be claimed in this application, in applications claiming priority from this application, or in related applications. Such claims, whether directed to a different invention or to the same invention, and whether broader, narrower, equal, or different in scope in comparison to the original claims, also are regarded as included within the subject matter of the inventions of the present disclosure. 

1-68. (canceled)
 69. A method of treating a cancer in a human subject comprising administering to the subject in need thereof an effective amount of therapeutic combination comprising a) an inducible cytokine polypeptide and b) a cellular therapy.
 70. The method of claim 69, where the cellular therapy comprises T-cell therapy.
 71. The method of 70, wherein the T-cell therapy comprises activated T cells.
 72. The method of claim 70, wherein the T-cell therapy comprises CAR-T cells.
 73. The method of claim 69, where the cellular therapy comprises NK cells.
 74. The method of claim 69, wherein the inducible cytokine polypeptide comprises IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23, TGF, interferon alpha, interferon beta, interferon gamma, TNF, TGFbeta, CXCL10, CCL19, CCL20, CCL21, or a mutein, a variant, an active fragment, or a subunit of any of the foregoing.
 75. The method of claim 69, wherein the inducible cytokine polypeptide comprises IL-2.
 76. The method of claim 69, wherein the inducible cytokine polypeptide comprises IL-12.
 77. The method of claim 69, wherein the inducible cytokine polypeptide comprises one polypeptide chain, or two or more polypeptide chains.
 78. The method of claim 75, wherein the inducible cytokine polypeptide comprises a) a cytokine polypeptide; b) a cytokine blocking moiety that inhibits cytokine receptor activating activity of the cytokine polypeptide; and c) a half-life extension domain; wherein the cytokine polypeptide is operably linked to the cytokine blocking moiety through a first linker comprising a cleavable peptide and the cytokine blocking moiety is operably linked to the half-life extension domain through a second linker.
 79. The method of claim 76, wherein the cytokine blocking moiety is a ligand-binding domain or fragment of a cognate receptor for the cytokine polypeptide or an antibody or antigen-binding fragment of an antibody that binds the cytokine polypeptide.
 80. The method of claim 76, wherein half-life extension domain is an immunoglobulin Fc, human serum albumin or a fragment thereof that binds neonatal Fc receptor, or an antigen-binding portion of an antibody that binds to FcRn or to human serum albumin.
 81. The method of claim 76, wherein a) the cytokine polypeptide is an IL-2 polypeptide; b) the cytokine blocking moiety is a IL-2-binding domain or fragment of an IL-2 receptor or an antibody or antigen-binding fragment of an antibody that binds IL-2; and c) the half-life extension domain is an immunoglobulin Fc, human serum albumin or a fragment thereof that binds neonatal Fc receptor, or an antigen-binding portion of an antibody that binds to FcRn or to human serum albumin.
 82. The method of claim 79, wherein the cytokine blocking moiety is a IL-2-binding domain or fragment of an IL-2 receptor, and the IL-2 receptor comprises IL-2Rα (CD25), IL-2Rβ (CD122), IL-2Rγ (CD132) or combinations thereof.
 83. The method of claim 79, wherein the cytokine blocking moiety is an antibody or antigen-binding fragment of an antibody that binds IL-2.
 84. The method of claim 76, wherein a) the cytokine polypeptide is an IL-12 polypeptide; b) the cytokine blocking moiety is a IL-12-binding domain or fragment of an IL-12 receptor or an antibody or antigen-binding fragment of an antibody that binds IL-12; and c) the half-life extension domain is an immunoglobulin Fc, human serum albumin or a fragment thereof that binds neonatal Fc receptor, or an antigen-binding portion of an antibody that binds to FcRn or to human serum albumin.
 85. The method of claim 79, wherein the cytokine blocking moiety is a IL-12-binding domain or fragment of an IL-12 receptor, and the IL-12 receptor comprises IL-12Rβ1, IL-12Rβ2 or combinations thereof.
 86. The method of claim 79, wherein the cytokine blocking moiety is an antibody or antigen-binding fragment of an antibody that binds IL-12.
 87. The method of claim 69, wherein the cancer is characterized by solid tumors.
 88. The method of claim 69, wherein the inducible cytokine polypeptide comprises a substrate for a protease and has at least about 10× less cytokine receptor activating activity relative to the polypeptide that contains the cytokine that is produced by protease cleavage of the inducible cytokine polypeptide.
 89. A therapeutic combination comprising a) an inducible cytokine polypeptide and b) a cellular therapy, in an amount effective to treat cancer in a human subject.
 90. A therapeutic combination comprising a) an inducible cytokine polypeptide, b) a cellular therapy, and c) an immune-oncology agent, in an amount effective to treat cancer in a human subject. 